Substituted pyrazolo[1,5-a]pyrimidines as Bruton&#39;s tyrosine kinase modulators

ABSTRACT

The invention is fused heterocyclic compounds of formula (I), and salts thereof, compositions thereof, and methods of use therefor. In particular, disclosed herein are certain fused heterocyclic compounds that can be useful for inhibiting protein kinase, including Bruton&#39;s tyrosine kinase (Btk), and for treating disorders mediated thereby.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/359,871, filed on Nov. 23, 2016, which is a continuation of U.S.patent application Ser. No. 14/951,494, now U.S. Pat. No. 9,556,188,filed on Nov. 25, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/723,417, now U.S. Pat. No. 9,447,106, filed onMay 27, 2015, which is a continuation of International Application No.PCT/CN2014/075943, filed on Apr. 22, 2014, which claims the benefit ofInternational Application No. PCT/CN2013/074728, filed on Apr. 25, 2013,the disclosures of which are hereby incorporated by reference in theirentirety for all purposes.

INTRODUCTION

Bruton's tyrosine kinase (Btk) belongs to the Tec tyrosine kinase family(Vetrie et al., Nature 361:226-233,1993; Bradshaw. Cell Signal,22:1175-84,2010). Btk is, primarily expressed in most hematopoieticcells such as B cells, mast cells and macrophages (Smith et al., J.Immunol. 152:557-565, 1994) and is localized in bone marrow, spleen andlymph node tissue. Btk plays important roles in B-cell receptor (BCR)and FcR signaling pathways, which involve in B-cell development,differentiation (Khan, Immunol. Res. 23: 147, 2001). Btk is activated byupstream Src-family kinases. Once activated, Btk in turn phosphorylatesPLC gamma, leading to effects on B-cell function and survival (Humphrieset al., J. Biol.Chem. 279: 37651,2004). These signaling pathways must beprecisely regulated. Mutations in the gene encoding Btk cause aninherited B-cell specific immunodeficiency disease in humans, known asX-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol.27: 199-227,2009). Aberrant BCR-mediated signaling may result indysregulated B-cell activation leading to a number of autoimmune andinflammatory diseases. Preclinical studies show that Btk deficient miceare resistant to developing collagen-induced arthritis. Moreover,clinical studies of Rituxan, a CD20 antibody to deplete mature B-cells,reveal the key role of B-cells in a number of inflammatory diseases suchas rheumatoid arthritis, systemic lupus erythematosus and multiplesclerosis (Gurcan et al., Inf. Immunopharmacol. 9: 10-25, 2009).Therefore, Btk inhibitors can be used to treat autoimmune and/orinflammatory diseases.

In addition, aberrant activating of Btk plays important role inpathogenesis of B-cell lymphomas indicating that inhibition of Btk isuseful in the treatment of Hematological malignancies (Davis et al.,Nature 463: 88-92, 2010). Preliminary clinical trial results showed thatthe Bruton's tyrosine kinase (Btk) inhibitor PCI-32765 was effective intreatment of several types of B-cell lymphoma (for example, 54^(th)American Society of Hematology (ASH) annual meeting abstract, December2012: 686 The Bruton's Tyrosine Kinase (Btk) Inhibitor, Ibrutinib(PCI-32765), Has Preferential Activity in the ABC Subtype ofRelapsed/Refractory De Novo Diffuse Large B-Cell Lymphoma (DLBCL);Interim Results of a Multicenter, Open-Label, Phase2 Study). Because Btkplays a central role as a mediator in multiple signal transductionpathways, inhibitors of Btk are of great interest as anti-inflammatoryand/or anti-cancer agents (Mohamed et al., Immunol. Rev. 228: 58-73,2009; Pan, Drug News perspect 21: 357-362, 2008; Rokosz et al., ExpertOpin. Ther. Targets 12: 883-903, 2008: Uckun et al., Anti-cancer AgentsMed. Chem. 7: 624-632, 2007; Lou et al., J. Med. Chem. 55(10):4539-4550, 2012).

Small molecule inhibitors of Btk are being developed foranti-inflammatory and anticancer therapy. Ibrutinib (PCI-32765, See:U.S. Pat. No. 7.514,444B2 and related documents, for examples,US2012053189A1; WO 2011153514; WO 2011046964; US2010254905A1;WO2010009342; WO2008121742; WO2008054827; US20080139582;US20080076921;U.S. Pat. No. 7.718,662B1: WO2007087068; US20100035841) is a first-inclass of Btk inhibitor, currently undergoing multiple clinical trials inrelapsed or refractory mantle cell lymphoma (MCL) and chroniclymphocytic leukaemia (CLL). Another Blk inhibitor entered clinicaltrials is AVL-292 (See, for example. US 20100249092; US20100029610;US2010016296; US20120077832; WO 2011090760; WO 2010028236; WO2009158571; WO2009051822; WO2010123870). Ono pharmaceuticals andMannkind Corporation have been doing clinical trials with their smallmolecular Btk inhibitors, respectively (See, for example, ONO-4059,WO2011152351; WO2007136790A2).

Other Btk inhibitors are also known. See, for example, US201270232054(LOCUS PHARMACEUTICALS, INC.), WO2010126960 (LOCUS PHARMACEUTICALS.INC.), WO 2011/162515 (HANMI HOLDINGS CO. LTD), WO2012135801 (UNIVERSITYOF UTAH RESEARCH FOUNDATION), Kim et al., Bioorg. Med. Chem. Lett. 21:6258-6263, 2011 (Pfizer), U.S. Pat. No. 8,084,620B2 (BMS), WO2002050071;WO2008116064; WO2010011837; WO 2011159857(BMS), US2012058996A1;US2012082702A1; US20100160303 (BMS), US2012129852A1 (BMS), WO 2011019780(BMS), WO2011029043; WO2011029046 (Biogen Idee), U.S. Pat. No. 7,393,848(CGI), US20060178367; US20060183746 (CGI), EP2068849 (CGI), WO2005005429; WO 2005014599; WO 2005047290; WO 2006053121; WO2008033834;WO 2008033858; WO 2006099075; WO 2008033854; WO 2008033857; WO2009039397 (CGI), WO 2009137596; WO 2010056875; WO 2010068788; WO201006S806; WO 2010068810 (CGI, GENENTECH), WO 2011140488; WO2012030990; WO 2012031004 (GILEAD & GENENTECH), US2012040961A1(DANA-FARBER CANCER INSTITUTE), WO 2005011597; WO 2008045627; WO2008144253 (IRM LLC), WO 2007140222; WO 2013008095 (NOVARTIS), WO20I2170976A2 (Merck), WO2012135944A1 (PHARMASCIENCE), US2010144705A1:US20120028981A1 (PRINCIPIA BIOPHARMA), WO 2010065898A2; WO 2012158795A1;WO 2012158764A1; WO 2012158810A1 (PRINCIPIA BIOPHARMA), US20090318448A1;US20100016301; US2009105209A1; US20100222325; US20100004231 (ROCHE), WO2012156334A1; WO 2012020008; WO 2010122038; WO 2010006970; WO2010006947; WO 2010000633; WO 2009077334; WO 2009098144 (ROCHE), WO2006065946; WO 2007027594; WO 2007027729 (VERTEX).

WO 2007/026720 A1 discloses that a ring-fused pyrazole compound offormula (A), wherein n represents 2 or 3; A represents the formula: —O—or the like; B represents a C₁₋₁₀alkylene group or the like; Crepresents a single bond or the formula; —O—; R¹-represents a hydrogenatom, a pyrrolidinyl group or the like; R⁴, R⁵ and R⁶ independentlyrepresents a hydrogen atom, a halogen atom or the like; D₁=D₂ representsthe formula; —CH═CH— or the like; H represents the formula: —O— or —NH—or the like; G represents a C1-10 alkylene group or the like; and R⁷represents a hydrogen atom, a phenyl group or the like, is useful as anLck kinase inhibitor;

SUMMARY OF THE INVENTION

The invention provides methods and compositions for inhibiting Btk andtreating disease associated with undesirable Btk activity (Btk-relateddiseases).

In one embodiment the invention provides Btk inhibitors or compounds offormula:

stereoisomers thereof, and pharmaceutically acceptable salts thereof,wherein:

A is a 5- or 6-membered aromatic ring comprising 0-3 heteroatoms of N, Sor O;

each W is independently —(CH₂)— or —C(O)—;

L is a bond, CH₂, NR¹², O, or S;

S/D is a single or double bond, and when a double bond, R⁵ and R⁷ areabsent;

m is 0, or an integer of 1-4;

n is 0, or an integer of 1-4, wherein when n is more than 1, each R² maybe different;

p is 0, or an integer of 1-2, wherein when p is 0, m is non-zero, andwhen p is more than 1, each R⁶ and each R⁷ may be different;

R¹, R⁴, R⁵, R⁶, and R⁷ are each independently H, halogen, heteroalkyl,alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl,heteroaryl, alkynyl, —CN, —NR¹³R¹⁴, —OR¹³, —COR¹³, CO₂R¹³, —CONR¹³R¹⁴,—C(═NR¹³)NR¹⁴R¹⁵, —NR¹³COR¹⁴, —NR¹³CONR¹⁴R¹⁵, —NR¹³CO₂R¹⁴, —SO₂R¹³,—NR¹³SO₂NR¹⁴R¹⁵, or —NR¹³SO₂R¹⁴, wherein the alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclylare optionally substituted with at least one substituent R¹⁶, wherein(R⁴ and R⁵), or (R⁴ and R⁶), or (R⁶ and R⁷), or (R⁶ and R⁶ when p is 2),together with the atoms to which they are attached, can form a ringselected from cycloalkyl, saturated or unsaturated heterocycle, aryl,and heteroaryl rings optionally substituted with at least onesubstituent R¹⁶;

R² is halogen, alkyl, —S—alkyl, —CN, —NR¹³R¹⁴, —OR¹³, —COR¹³, —CO₂R¹³,—CONR¹³R¹⁴, —C(═NR¹³)NR¹⁴R¹⁵, —NR¹³COR¹⁴, —NR¹³CONR¹⁴R¹⁵, —NR¹³CO₂R¹⁴,—SO₂R¹³, —NR¹³SO₂NR¹⁴R¹⁵, or —NR¹³SO₂R¹⁴;

R¹² is H or lower alkyl;

R¹³, R¹⁴ and R¹⁵ are each independently H, heteroalkyl, alkyl, alkenyl,alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, orheteroaryl; wherein (R¹³ and R¹⁴), and/or (R¹⁴ and R¹⁵) together withthe atom(s) to which they are attached, each can form a ring selectedfrom cycloalkyl, saturated or unsaturated heterocycle, aryl, andheteroaryl rings optionally substituted with at least one substituentR¹⁶;

R¹⁶ is halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclyl, oxo, —CN, —OR′,—NR′R″, —COR′,—CO₂R′, —CONR′R″,—C(═NR′)NR″R′″, —NR′COR″, —NR′CONR′R″, —NR′CO₂R″, —SO₂R′, —SO₂aryl,—NR′—SO₂NR″R′″, or —NR′SO₂R″ wherein R′, R″ and R′″ are independentlyhydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclyl, wherein (R′ and R″), and/or (R″ and R′″) together with theatoms to which they are attached, can form a ring selected fromcycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroarylrings.

In exemplary particular embodiments:

(a) S/D is a double bond and R⁵ and R⁷ are absent;

(b) R¹ is H, halogen, alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl,aryl, saturated or unsaturated heterocyclyl, heteroaryl, wherein thealkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated orunsaturated heterocyclyl are optionally substituted with at least onesubstituent R¹⁶;

(c) p is 1 and m is 0, 1 or 2, preferably 0 or 1;

(d) A is phenyl;

(e) each R² is independently halogen, lower alkyl, or lower alkoxy

(f) R⁴ and R⁶, together with the atoms to which they are attached, forma ring selected from cycloalkyl, saturated or unsaturated heterocycle,aryl, and heteroaryl rings optionally substituted with at least onesubstituent R¹⁶,

(g) R⁴ and R⁶, together with the atoms to which they are attached, forma ring of formula:

wherein:Q is —CH₂—; J is —CH₂—; and d and b are each independently 0, or aninteger of 1-4:

(h) S/D is a single bond.

(i) p is 0 and R⁶ and R⁷ are absent.

The invention includes all combinations of the recited particularembodiments, such as (a)-(i), supra, as if each combination had beenlaboriously separately recited.

In exemplary combinations of particular embodiments:

(i) S/D is a double bond and R⁵ and R⁷ are absent; R¹ is H, halogen,alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated orunsaturated heterocyclyl, heteroaryl, wherein the alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturatedheterocyclyl are optionally substituted with at least one substituentR¹⁶; and R¹⁶ is halogen, lower alkyl, or lower alkoxy;

(ii) S/D is a double bond and R⁵ and R⁷ are absent; p is 1 and m is 0 or1 (or 2);

(iii) S/D is a double bond and R⁵ and R⁷ are absent; p is 1 and m is 0or 1 (or 2); A is phenyl; and each R² is independently halogen, loweralkyl, or lower alkoxy (see, formula II);

(iv) S/D is a double bond and R⁵ and R⁷ are absent; and R⁴ and R⁶,together with the atoms to which they are attached, form a ring selectedfrom cycloalkyl, saturated or unsaturated heterocycle, aryl, andheteroaryl rings optionally substituted with at least one substituentR¹⁶.

(v) S/D is a double bond and R⁵ and R⁷ are absent; R⁴ and R⁶, togetherwith the atoms to which they are attached, form a ring selected fromcycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroarylrings optionally substituted with at least one substituent R¹⁶; A isphenyl; and each R² is independently halogen, lower alkyl, or loweralkoxy.

(vi) S/D is a double bond and R⁵ and R⁷ are absent; R⁴ and R⁶, togetherwith the atoms to which they are attached, form a ring selected fromcycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroarylrings optionally substituted with at least one substituent R¹⁶; p is 1and in 0 or 1 (or 2); A is phenyl; each R² is independently halogen,lower alkyl, or lower alkoxy; and the R⁴-R⁶ ring is of formula:

wherein Q is —CH₂—; J is —CH₂—; and d and b are each independently 0, oran integer of 1-4 (see, formula III);

(vii) S/D is a double bond and R⁵ and R⁷ are absent; R⁴ and R⁶, togetherwith the atoms to which they are attached, form a ring selected fromcycloalkyl. saturated or unsaturated heterocycle, aryl, and heteroarylrings optionally substituted with at least one substituent R¹⁶; p is 1and m is 0 or 1 (or 2); A is phenyl; each R² is independently halogen,lower alkyl, or lower alkoxy; and the R⁴-R⁶ ring is of formula:

wherein Q is —CH₂—; J is —CH₂—; and d and b are each independently 0, oran integer of 1-4; and R¹ is H, halogen, alkoxy, heteroalkyl, alkyl,alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl,heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,aryl, and saturated or unsaturated heterocyclyl are optionallysubstituted with at least one substituent R¹⁶;

(viii) S/D is a single bond; p is 1 and m is 0, 1 or 2; A is phenyl;each R² is independently halogen, lower alkyl, or lower alkoxy (see,formula IV);

(ix) S/D is a single bond; p is 1 and m is 0, 1 or 2; A is phenyl; eachR² is independently halogen, lower alkyl, or lower alkoxy, and R¹ is H,halogen, alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl,saturated or unsaturated heterocyclyl, heteroaryl, wherein the alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated orunsaturated heterocyclyl are optionally substituted with at least onesubstituent R¹⁶; and R¹⁶ is halogen, lower alkyl, or lower alkoxy;

(x) S/D is a single bond; p is 0 and R⁶ and R⁷ are absent; A is phenyl;and each R² is independently halogen, lower alkyl, or lower alkoxy (see,formula V);

(xi) S/D is a single bond; p is 0 and R⁶ and R⁷ are absent; A is phenyl;and each R² is independently halogen, lower alkyl, or lower alkoxy, andR¹ is H, halogen, alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl,saturated or unsaturated heterocyclyl, heteroaryl, wherein the alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl aryl, and saturated orunsaturated heterocyclyl are optionally substituted with at least onesubstituent R¹⁶; and R¹⁶ is halogen, lower alkyl, or lower alkoxy.

In particular embodiments the invention provides compounds of formulaII, III, IV and V, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof, wherein substituents are as defined herein:

The invention also provides compounds of the examples herein, or ofTable I, II or III, (below), stereoisomers thereof, and pharmaceuticallyacceptable salts thereof.

The invention also provides subject compounds having a Btk-inhibitingactivity corresponding to a IC50 of 10 uM or less in the BTK KINASEASSAY.

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a subject compound in unit dosageform and one or more pharmaceutically acceptable carriers.

The invention also provides combinations comprising a therapeuticallyeffective amount of a subject compound and a different agenttherapeutically active against an autoimmune and/or inflammatorydisease.

The invention also provides methods treating a Btk related disease, ordisease associated with undesirable Btk activity, particularly anallergic disease, an autoimmune disease (e.g. rheumatoid arthritis), aninflammatory disease, or cancer (e.g. a B-cell proliferative disorder,such as chronic lymphocytic lymphoma, non-Hodgkin's lymphoma, diffuselarge B cell lymphoma, mantle cell lymphoma, follicular lymphoma orchronic lymphocytic leukemia), which methods generally compriseadministering to a mammal in need thereof an effective amount of asubject compound, an N-oxide thereof or a prodrug thereof, andoptionally detecting a resultant amelioration of disease or symptomthereof, or Bkt-inhibition.

The invention also provides pharmaceutical compositions comprising asubject compound in unit dosage, administrable form, and methods ofinducing autophagy, comprising administering to a person in need thereofan effective amount of a subject compound or composition.

The invention also provides the subject compounds for use as amedicament, and use of the subject compounds in the manufacture of amedicament for the treatment of a Btk related disease.

DESCRIPTION OF PARTICULAR EMBODIMENTS OF THE INVENTION

Disclosed herein are compounds that can inhibit tyrosine kinases, suchas Btk, Blk, Bmx, EGFR, ERBB2, ERBB4, Itk, Jak3, Tec and Txk kinases.

The following words, phrases and symbols are generally intended to havethe meanings as set forth below, except to the extent that the contextin which they are used indicates otherwise. The following abbreviationsand terms have the indicated meanings throughout.

The term “alkyl” refers to a hydrocarbon group selected from linear andbranched saturated hydrocarbon groups of 1-18, or 1-12, or 1-6 carbonatoms. Examples of the alkyl group include methyl, ethyl, 1-propyl orn-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl(“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl ors-butyl (“s-Bu”), and 1,1-dimethylethyl ort-butyl (“t-Bu”). Otherexamples of the alkyl group include 1-pentyl, 2-pentyl, 3-pentyl,2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl,1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl,2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups.

Lower alkyl means 1-8, preferably 1-6, more preferably 1-4 carbon atoms;lower alkenyl or alkynyl means 2-8,2-6 or 2-4 carbon atoms.

The term “alkenyl” refers to a hydrocarbon group selected from linearand branched hydrocarbon groups comprising at least one C═C double bondand of 2-18, or 2-12, or 2-6 carbon atoms. Examples of the alkenyl groupmay be selected from ethenyl or vinyl, prop-1-enyl, prop-2-enyl,2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl,buta-1,3-dienyl, 2-melthylbuta-1,3-diene, hex-1-enyl, hex-2-enyl,hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

The term “alkynyl” refers to a hydrocarbon group selected from linearand branched hydrocarbon group, comprising at least one C≡C triple bondand of 2-18, or 2-12, or 2-6 carbon atoms. Examples of the alkynyl groupinclude ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl,2-butynyl, and 3-butynyl groups.

The term “cycloalkyl” refers to a hydrocarbon group selected fromsaturated and partially unsaturated cyclic hydrocarbon groups,comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic)groups. For example, the cycloalkyl group may be of 3-12, or 3-8, or 3-6carbon atoms. Even further for example, the cycloalkyl group may be amonocyclic group of 3-12, or 3-8, or 3-6 carbon atoms. Examples of themonocyclic cycloalkyl group include cyclopropyl, cyclobutyl,cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-ethyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, and cyclododecyl groups. Examples of thebicyclic cycloalkyl groups include those having 7-12 ring atoms arrangedas a bicycle ring selected from [4,4], [4,5], [5,5], [5,6]and [6,6] ringsystems, or as a bridged bicyclic ring selected frombicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3,2,2]nonane.The ring may be saturated or have at least one double bond (i.e.partially unsaturated), but is not fully conjugated, and is notaromatic, as aromatic is defined herein.

The term “Aryl” herein refers to a group selected from: 5- and6-membered carbocyclic aromatic rings, for example, phenyl; bicyclicring systems such as 7-12 membered bicyclic ring systems wherein atleast one ring is carbocyclic and aromatic, selected, for example, fromnaphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ringsystems such as 10-15 membered tricyclic ring systems wherein at leastone ring is carbocyclic and aromatic, for example, fluorene.

For example, the aryl group is selected from 5- and 6-memberedcarbocyclic aromatic rings fused to a 5- to 7-membered cycloalkyl orheterocyclic ring optionally comprising al least one heteroatom selectedfrom N, O, and S, provided that the point of attachment is at thecarbocyclic aromatic ring when the carbocyclic aromatic ring is fusedwith a heterocyclic ring, and the point of attachment can be at thecarbocyclic aromatic ring or al the cycloalkyl group when thecarbocyclic aromatic ring is fused with a cycloalkyl group. Bivalentradicals formed from substituted benzene derivatives and having the freevalences at ring atoms are named as substituted phenylene radicals.Bivalent radicals derived from univalent polycyclic hydrocarbon radicalswhose names end in “-yl” by removal of one hydrogen atom from the carbonatom with the free valence are named by adding “-idene” to the name ofthe corresponding univalent radical, e.g., a naphthyl group with twopoints of attachment is termed naphthylidene. Aryl, however, does notencompass or overlap with heteroaryl, separately defined below. Hence,if one or more carbocyclic aromatic rings are fused with a heterocyclicaromatic ring, the resulting ring system is heteroaryl, not aryl, asdefined herein.

The term “halogen” or “halo” refers to F, Cl, Br or I.

The term “heteroalkyl” refers to alkyl comprising at least oneheteroatom.

The term “heteroaryl” refers to a group selected from:

5- to 7-membered aromatic, monocyclic rings comprising 1, 2, 3 or 4heteroatoms selected from N, O, and S, with the remaining ring atomsbeing carbon;

8- to 12-membered bicyclic rings comprising 1, 2, 3 or 4 heteroatoms,selected from N, O, and S, with the remaining ring atoms being carbonand wherein at least one ring is aromatic and at least one heteroatom ispresent in the aromatic ring; and

11-to 14-membered tricyclic rings comprising 1, 2, 3 or4 heteroatoms,selected from N, O, and S, with the remaining ring atoms being carbonand wherein at least one ring is aromatic and at least one heteroatom ispresent in an aromatic ring.

For example, the heteroaryl group includes a 5- to 7-memberedheterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring.For such fused, bicyclic heteroaryl ring systems wherein only one of therings comprises at least one heteroatom, the point of attachment may beat the heteroaromatic ring oral the cycloalkyl ring,

When the total number of S and O atoms in the heteroaryl group exceeds1, those heteroatoms are not adjacent to one another. In someembodiments, the total number of S and O atoms in the heteroaryl groupis not more than 2. In some embodiments, the total number of S and Oatoms in the aromatic heterocycle is not more than 1.

Examples of the heteroaryl group include, but are not limited to, (asnumbered from the linkage position assigned priority 1) pyridyl (such as2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl,2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl,isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl,thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzoimidazolyl,indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl,pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl,pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl),pyrazolopyridinyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl(such as benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl,1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl,1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl,1-thia-3,4-diazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, furopyridinyl, benzothiazolyl (such asbenzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl) and5,6,7,8-tetrahydroisoquinoline.

The term “heterocyclic” or “heterocycle” or “heterocyclyl” refers to aring selected from 4- to 12-membered monocyclic, bicyclic and tricyclic,saturated and partially unsaturated rings comprising at least one carbonatoms in addition to 1,2,3 or 4 heteroatoms, selected from oxygen,sulfur, and nitrogen. “Heterocycle” also refers to a 5- to 7-memberedheterocyclic ring comprising at least one heteroatom selected from N, O,and S fused with 5-, 6-, and/or 7-membered cycloalkyl, carbocyclicaromatic or heteroaromatic ring, provided that the point of attachmentis at the heterocyclic ring when the heterocyclic ring is fused with acarbocyclic aromatic or a heteroaromatic ring, and that the point ofattachment can be at the cycloalkyl or heterocyclic ring when theheterocyclic ring is fused with cycloalkyl.

“Heterocycle” also refers to an aliphatic spirocyclic ring comprising atleast one heteroatom selected from N, O, and S, provided that the pointof attachment is at the heterocyclic ring. The rings may be saturated orhave at least one double bond (i.e. partially unsaturated). Theheterocycle may be substituted with oxo. The point of the attachment maybe carbon or heteroatom in the heterocyclic ring. A heterocyle is not aheteroaryl as defined herein.

Examples of the heterocycle Include, but not limited to, (as numberedfrom the linkage position assigned priority 1) 1-pyrrol idinyl,2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl,2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl,azctidinyl, oxctanyl, thteianyl, 1,2-dithietanyl, 1,3-dithietanyl,dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl,piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl,thiepanyl, 1,4-oxathianyl, 1,4-dioxepany 1,4-oxathiepanyl,1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepane1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl,dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl,1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl,dithianyl, dithiblanyl, pyrazolidinylimidazolinyl, pyrimidinonyl,1,1-dioxo-thiomorpholinyl, 3-azabicyco [3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl and azabicyclo[2.2.2]hexanyl. Substitutedheterocycle also includes ring systems substituted with one or more oxomoieties, such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.

Substituents are selected from: halogen, —R′,—OR′, ═O, ═NR′, ═N—OR′,—NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR′″, —NR″CO₂R′,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —SO₂R′,—SO₂NR′R″, —NR″SO₂R, —CN and —NO₂, —N₃, —CH(Ph)₂, perfluoro(C1-C4)alkoxyand perfluoro(C1-C4)alkyl, in a number ranging from zero to three, withthose groups having zero, one or two substituents being particularlypreferred. R′, R″ and R′″ each independently refer to hydrogen,unsubstituted (C1-C8)alkyl and heteroalkyl, unsubstituted aryl, arylsubstituted with one to three halogens, unsubstituted alkyl, alkoxy orthioalkoxy groups, or aryl-(C1-C4)alkyl groups. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6- or 7-membered ring. Hence, —NR′R″includes 1-pyrrolidinyl and 4-morpholinyl, “alkyl” includes groups suchas triholoalkyl (e.g., —CF₃ and —CH₂CF₃), and when the aryl group is1,2,3,4-tetrahydro naphthalene, it may be substituted with a substitutedor unsubstituted (C3-C7)spirocycloalkyl group. The(C3-C7)spirocycloalkyl group may be substituted in the same manner asdefined herein for “cycloalkyl”.

Preferred substituents are selected from: halogen. —R′—OR′, ═O, —NR′R″,—SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR″CO₂R′, —NR′—SO₂NR″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN and —NO₂, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, where R′ and R″ are as defined above.

The term “fused ring” herein refers to a polycyclic ring system, e.g., abicyclic or tricyclic ring system, in which two rings share only tworing atoms and one bond in common. Examples of fused rings may comprisea fused bicyclic cycloalkyl ring such as those having from 7 to 12 ringatoms arranged as a bicyclic ring selected from [4,4], [4,5], [5,5],[5,6] and [6,6] ring systems as mentioned above; a fused bicylclic arylring such as 7 to 12 membered bicyclic aryl ring systems as mentionedabove, a fused tricyclic aryl ring such as 10 to 15 membered tricyclicaryl ring systems mentioned above; a fused bicyclic heteroaryl ring suchas 8- to 12-membered bicyclic heteroaryl rings as mentioned above, afused tricyclic heteroaryl ring such as 11- to 14-membered tricyclicheteroaryl rings as mentioned above; and a fused bicyclic or tricyclicheterocyclyl ring as mentioned above.

The compounds may contain an asymmetric center and may thus exist asenantiomers. Where the compounds possess two or more asymmetric centers,they may additionally exist as diastereomers. Enantiomers anddiastereomers fall within the broader class of stereoisomers. All suchpossible stereoisomers as substantially pure resolved enantiomers,racemic mixtures thereof, as well as mixtures of diastereomers areintended to be included. All stereoisomers of the compounds and/orpharmaceutically acceptable salts thereof are intended to be included.Unless specifically mentioned otherwise, reference to one isomer appliesto any of the possible isomers. Whenever the isomeric composition isunspecified, all possible isomers are included.

The term “substantially pure” means that the target stereoisomercontains no more than 35%, such as no more than 30%, further such as nomore than 25%, even further such as no more than 20%, by weight of anyother stereoisomers). In some embodiments, the term “substantially pure”means that the target stereoisomer contains no more than 10%, forexample, no more than 5%, such as no more than 1%, by weight of anyother stereoisomer(s).

When compounds contain olefin double bonds, unless specified otherwise,such double bonds are meant to include both E and Z geometric isomers.

Some of the compounds may exist with different points of attachment ofhydrogen, referred to as tautomers. For example, compounds includingcarbonyl —CH₂C(O)— groups (keto forms) may undergo tautomerism to formhydroxyl —CH═C(OH)— groups (enol forms). Both keto and enol forms,individually as well as mixtures thereof, are also intended to beincluded where applicable.

It may be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified (hereinafter separated) tothe desired degree of homogeneity by the techniques common in the art.Typically such separations involve multiphase extraction,crystallization from a solvent or solvent mixture, distillation,sublimation, or chromatography. Chromatography can involve any number ofmethods including, for example: reverse-phase and normal phase; sizeexclusion; ion exchange; high, medium and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (“SMB”) and preparative thin or thick layer chromatography,as well as techniques of small scale thin layer and flashchromatography. One skilled in the art will apply techniques most likelyto achieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., a substantially pure enantiomer, may beobtained by resolution of the racemic mixture using a method such asformation of diastereomeric using optically active resolving agents(Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York:John Wiley & Sons. Inc., 1994; Lochmuller, C. H., et al.“Chromatographic resolution of enantiomers: Selective review.” J.Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: Wainer,Irving W., Ed. Drug Stereochemistry: Analytical Methods andPharmacology. New York: Marcel Dekker, Inc., 1993.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, selected, for example, from hydrochlorates,phosphates, diphosphates; hydrobromates, sulfates, sulfinates, andnitrates: as well as salts with organic acids, selected, for example,from malates, maleates, fumarates, tartrates, succinates, citrates,lactates, methane sulfonates, p-toluenesulfonates,2-hydroxyethylsulfonates, benzoates, salicylates, stearates, alkanoatessuch as acetate, and salts with HOOC—(CH₂)n-COOH, wherein n is selectedfrom 0 to 4. Similarly, examples of pharmaceutically acceptable cationsinclude, but are not limited to, sodium, potassium, calcium, aluminum,lithium, and ammonium.

In addition, if a compound is obtained as an acid addition salt, thefree base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt, such as apharmaceutically acceptable addition salt, may be produced by dissolvingthe free base in a suitable organic solvent and treating the solutionwith an acid, in accordance with conventional procedures for preparingacid addition salts from base compounds. Those skilled in the art willrecognize various synthetic methodologies that may be used without undueexperimentation to prepare non-toxic pharmaceutically acceptableaddition salts,

“Treating,” “treat,” or “treatment” refers to administering at least onecompound and/or at least one stereoisomer thereof, and/or at least onepharmaceutically acceptable salt thereof to a subject in recognized needthereof that has, for example, cancer.

An “effective amount” refers to an amount of at least one compoundand/or at least one stereoisomer thereof, and/or at least onepharmaceutically acceptable salt thereof effective to “treat” a diseaseor disorder in a subject, and that will elicit, to some significantextent, the biological or medical response of a tissue, system, animalor human that is being sought, such as when administered, is sufficientto prevent development of, or alleviate to some extent, one or more ofthe symptoms of the condition or disorder being treated. Thetherapeutically effective amount will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

The term “at least one substituent” includes, for example, from 1 to 4,such as from 1 to 3, further as 1 or 2, substituents. For example, “atleast one substituent R¹⁶” herein includes from 1 to 4, such as from 1to 3, further as 1 or 2, substituents selected From the list of R¹⁶ asdescribed herein.

The invention provides compounds of formula:

stereoisomers thereof, and pharmaceutically acceptable salts thereof.

R¹ (and R⁴, R⁵, R⁶, and R⁷) are each independently H, halogen,heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturatedheterocyclyl, heteroaryl, alkynyl, —CN, —NR¹³R¹⁴, —OR¹³, —COR¹³,—CO₂R¹³, —CONR¹³R¹⁴, —C(═NR¹³)NR¹⁴R¹⁵, —NR¹³COR¹⁴, —NR¹³CONR¹⁴R¹⁵,—NR¹³CO₂R¹⁴, —SO₂R¹³, —NR¹³SO₂NR¹⁴R¹⁵, or —NR¹³SO₂R¹⁴, wherein thealkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated orunsaturated heterocyclyl are optionally substituted with at least onesubstituent R¹⁶.

R¹³, R¹⁴ and R¹⁵ are each independently H, heteroalkyly, alkyl, alkenyl,alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, orheteroaryl; wherein (R¹³ and R¹⁴), and/or (R¹⁴ and R¹⁵) together withthe atom(s) to which they are attached, each can form a ring selectedfrom cycloalkyl, saturated or unsaturated heterocycle, aryl, andheteroaryl rings optionally substituted with at least one substituentR¹⁶. In particular embodiments R¹³, R¹⁴ and R¹⁵ are each independentlyH, lower alkyl, or lower alkoxy.

R¹⁶ is halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclyl, oxo, —CN, —OR′—, —NR′R″, —COR′, —CO₂R′, —CONR′R″,—C(═NR′)NR″R′″, —NR′COR″, —NR′CONR′R″, —NR′CO₂R″, —SO₂R′, —SO₂aryl,—NR′SO₂NR″R′″, or —NR′SO₂R″, wherein R′, R″, and R′″ are independentlyhydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclyl, wherein (R′ and R″), and/or (R″ and R′″) together with theatoms to which they are attached, can form a ring selected fromcycloalkyl. saturated or unsaturated heterocycle, aryl, and heteroarylrings.

R¹⁶ of R¹ in particular embodiments is halogen, lower, alkyl, or loweralkoxy.

R¹ in particular embodiments is an optionally hetero-, optionallysubstituted hydrocarbon selected from heteroalkyl, alkyl, alkenyl,cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl,wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, andsaturated or unsaturated heterocyclyl are optionally substituted with atleast one substituent R¹⁶, wherein cyclic structures are preferably 3-8membered ring structures comprising 0-3 heteroatoms of N, S or O, andthe aryl is preferably a 5- or 6-membered aromatic ring comprising 0-3heteroatoms of N, S or O, wherein the hydrocarbon is preferably a C1-C12or C1-C8 hydrocarbon.

R¹ in particular embodiments is heteroalkyl, alkyl, alkenyl, cycloalkyl,aryl, saturated or unsaturated heterocyclyl, heteroaryl, wherein thealkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated orunsaturated heterocyclyl are optionally substituted with at least onesubstituent R¹⁶.

R¹ in particular embodiments is lower alkyl or alkenyl, optionallycyclic and optionally substituted, particularly with halogen, loweralkyl, or lower alkoxy, and comprising 0-3 heteroatoms of N, S or O.Examples include methylcyclopropyl, cyclohexyl, cyclopentyl,methoxyethyl, halide, methyl, ethyl, propyl and butyl. Other exemplaryR¹ moieties include 5-membered aromatic rings like pyrrole, pyrazole,imidazole, furan and hydrogenations thereof (e.g. pyrrolidine,pyrazolidine, imidazolidine, tetrahydrofuran), and 6-membered rings likebenzene (phenyl), pyridine, pyran, diazines, triazines and tetrazines,and hydrogenations thereof (e.g. cyclohexane, di- andtetra-hydropyridine, piperidine, tetrahydropyran, etc.), each of whichmay be substituted, particularly with halogen, lower alkyl, or loweralkoxy.

L is a bond, CH₂, NR¹², O, or S, wherein R¹² is H or lower alkyl, e.g.methyl.

A is a 5- or 6-membered aromatic ring comprising 0-3 heteroatoms of N, Sor O. Preferred 5-membered aromatic rings include pyrrole, pyrazole,imidazole, furan and 6-membered rings include benzene (phenyl),pyridine, pyran, diazines, triazines and tetrazines.

n is 0, 1, 2, 3 or 4, wherein when n is more than 1, each R² may bedifferent. In particular embodiments n is 0 (i.e. A is unsubstituted).

R² is halogen, alkyl, —S-alkyl, —CN, —NR¹³R¹⁴, —OR¹³, —COR¹³, —CO₂R¹³,—CONR¹³R¹⁴, —C(═NR¹³)NR¹⁴R¹⁵, —NR¹³COR¹⁴, —NR¹³CONR¹⁴R¹⁵, —NR¹³CO₂R¹⁴,—SO₂R¹³, —NR¹³SO₂NR¹⁴R¹⁵, or —NR¹³SO₂R¹⁴; wherein R¹³, R¹⁴ and R¹⁵ areeach independently H, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl,saturated or unsaturated heterocyclyl, aryl, or heteroaryl; wherein (R¹³and R¹⁴), and/or (R¹⁴ and R¹⁵) together with the atom(s) to which theyare attached, each can form a ring selected from cycloalkyl, saturatedor unsaturated heterocycle, aryl, and heteroaryl rings optionallysubstituted with at least one substituent R¹⁶.

R² in particular embodiments is halogen, alkyl, —S-alkyl, —CN, —NR¹³R¹⁴,—OR¹³, —COR¹³, —CO₂R¹³, —CONR¹³R¹⁴, —C(═NR¹³)NR¹⁴R¹⁵, —NR¹³COR¹⁴,—NR¹³CONR¹⁴R¹⁵, —NR¹³CO₂R¹⁴, —SO₂R¹³, —NR¹³SO₂NR¹⁴R¹⁵, or —NR¹³SO₂R¹⁴,preferably wherein the alkyl (including —S—alkyl) is lower alkyl, andR¹³, R¹⁴ and R¹⁵ are each independently H, lower alkyl, or lower alkoxy.

R² in particular embodiments is halogen, lower alkyl, or lower alkoxy.

each W is independently —(CH₂)— or —C(O)—, wherein if m is 2,3 or 4,preferably no more than one W is carbonyl;

S/D is a single or double bond, and when a double bond, R⁵ and R⁷ areabsent;

m is 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, and in particularembodiments 0, 1 or 2, or 0 or 1.

p is 0 (and R⁶ and R⁷ are absent); or an integer of 1-2, wherein when pis 0, m is non-zero, and when p is more than 1,each R⁶ and each R⁷ maybe different; generally p+m is 1, 2, 3 or 4, preferably 1, 2 or 3, andin particular embodiments 1.

In particular embodiments p is 2 and m is 0 or 1; p is 1 and m is 0 or 1(or 0, 1 or 2); or p is 0 and m is 1 or 2 (or 1, 2 or 3).

R⁴ and R⁵, or R⁴ and R⁶, or R⁶ and R⁷, or R⁶ and R⁶ (when p is 2),together with the atoms to which they are attached, can form a ringselected from cycloalkyl, saturated or unsaturated heterocycle, aryl,and heteroaryl rings optionally substituted with at least onesubstituent R¹⁶. These rings are generally 4-8-membered and include5-membered aromatic rings like pyrrole, pyrazole, imidazole, furan andhydrogenations thereof (e.g. pyrrolidine, pyrazolidine, imidazolidine,tetrahydrofuran), and 6-membered rings like benzene (phenyl), pyridine,pyran, diamines, triazines and tetrazines, and hydrogenations thereof(e.g. cyclohexane, di- and tetra-hydropyridine, piperidine,tetrahydropyran, etc.), each of which may be unsubstituted orsubstituted, particularly with halogen, lower alkyl, lower alkoxy,—COR′, or NR′COR″, wherein R′, R″ are substituted or unsubstitutedalkenyl.

R⁴ and R⁵ (or R⁶ and R⁷, or R⁶ and R⁶, when p is 2), in particularembodiments form piperidine, azacycloheptanyl, or azetidine, optionallysubstituted, particularly N-substituted with moieties such as benzyl,acyl, acryloyl, etc.

R⁴ and R⁶, in particular embodiments, together with the atoms to whichthey are attached, form a ring of formula:

wherein:Q is —CH₂—; J is —CH₂—; and d and b are each independently 0, or aninteger of 1-4.

R⁴ and R⁶ in particular embodiments form phenyl, piperidine,azacycloheptenyl, pyrrolidine, optionally substituted, particularlyN-substituted with moieties such as benzyl, acyl, acryloyl,methylamine-acryloyl, etc.

The invention includes all combinations of the recited particular andpreferred embodiments as if each combination had been laboriouslyseparately recited. For example, in particular embodiments, supra, A isphenyl; W is —(CH₂)—; L is O; S/D is a single bond; m is 1; n is 0; p is1; R¹ is phenyl; R² is absent; R⁵ is H; and R⁶ and R⁷ are H; yieldingthe combination:

R⁴, supra, includes N-containing C1-C8 alkyl, N-containing C3-C8cycloalkyl and phenyl, for example, methylamine, aniline, azetidine,pyrrolidine, piperidine, azacycloheptenyl, each optionally, substituted,particularly N-substituted with moieties such as benzyl, acyl, acryloyl,substituted-acryloyl, propiolyl, substituted-propiolyl, etc., such asstructure combinations:

In particular examples, R⁴ is 1-acryloylpiperidin-4-yl (e.g. compound27) or 1-(but-2-ynoyl) piperidin-4-yl (e.g. compound 176).

The invention also provides all the compounds of the examples herein,and of Table I, II and III, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof.

The subject compounds and stereoisomers thereof, and pharmaceuticallyacceptable salts thereof may be employed alone or in combination with atleast one oilier therapeutic agent for treatment. In some embodiments,the compounds, stereoisomers thereof, and pharmaceutically acceptablesalts thereof can be used in combination with at least one additionaltherapeutic agent. The at least one additional therapeutic agent can be,for example, selected from anti-hyperproliferative, anti-cancer, andchemotherapeutic agents. The compound and/or one pharmaceuticallyacceptable salt disclosed herein may be administered with the at leastone other therapeutic agent in a single dosage form or as a separatedosage form. When administered as a separate dosage form, the at leastone other therapeutic agent may be administered prior to, at the sametime as, or following administration of the compound and/or onepharmaceutically acceptable salt disclosed herein.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer, regardless of mechanism of action. Chemotherapeuticagents include compounds used in “targeted therapy” and conventionalchemotherapy. Suitable chemotherapeutic agents can be, for example,selected from: agents that induce apoptosis; polynucleotides (e.g.,ribozymes); polypeptides (e.g., enzymes); drugs; biological mimetics;alkaloids; alkylating agents; antitumor antibiotics; antimetabolites;hormones; platinum compounds; monoclonal antibodies conjugated withanticancer drugs, toxins, and/or radionuclides; biological responsemodifiers (e.g., interferons, such as IFN-α and interleukins, such asIL-2); adoptive immunotherapy agents; hematopoietic growth factors:agents that induce tumor cell differentiation (e.g., all-trans-retinoicacid); gene therapy reagents; antisense therapy reagents andnucleotides; tumor vaccines; and inhibitors of angiogenesis.

Examples of chemotherapeutic agents include Erlotinib (TARCEVA®,Genentech/OSI Pharm.); Bortezomib (VELCADE®, Millennium Pharm.):Fuivestrant (FASLODEX®, AstraZeneca); Sunitinib (SUTENT®, Pfizer);Lerrozole (FEMARA®, Novartis); Imatinib mesylate (GLEEVEC®, Novartis);PTK787/ZK 222584 (Novartis); Oxaliplatin (Eloxatin®, Sanofi); 5-FU(5-fluorouracil); Leucoyorin; Rapamycin (Sirolimus, RAPAMUNE®, Wyeth);Lapatinib (TYKERB®, GSK5720I6, Glaxo Smith Kline); Lonafarnib (SCH66336); Sorafenib (NEXAVAR®, Bayer); Irinotecan (CAMPTOSAR®, Pfizer) andGefitinib (IRESSA®, AstraZeneca); AG1478, AG1571 (SU 5271, Sugen);alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines suchas benzodopa, carboquone, meturedopa, and uredopa; ethylenimines andmethylamelamines such as altreiamine, triethylenemelamine,triethylenephosphoramide, triethylenethiophosphoramide andtrimethylomelamine; acetogenins (such as bullatacin and bullatacinone);a camptothecin (such as the synthetic analog topotecan); bryostatin;callystatin; CC-1065 and its adozelesin, carzelesin and bizelesinsynthetic analogs; cryptophycins (such as cryptophycin 1 andcryptophycin 8); dolastalin; duocarmycin and the synthetic analogsthereof, such as KW-2189 and CB1-TM1; eleutherobin; pancratistatin; asarcodictyin; spongistatin; nitrogen mustards such as chlorambucil,chlomaphazine, chlorophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine,nimustine, and ranimnustine; antibiotics such as the enediyneantibiotics (e.g., calicheamicin, such as calicheamicin gamma II andcalicheamicin omegall (Angew Chem. Intl. Ed. Engl, (1994) 33:183-186);dynemicin, such as dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores, aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepiliostane, testolactone; anti-adrenals such as ammoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminol evulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitogunzone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethyl amine; trichothecenes (such as T-2 toxin,verracurin A, roridin A andanguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”): cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®(paclitaxel; Bristol-Myers Squibb Oncology, Princeton; N.J.), ABRAXANE®(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partner, Schaumberg, Ill.), andTAXOTERE® (doxetaxel; Rhone-Poulene Rorer, Antony, France);chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin;vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate;daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11;topoisomer use inhibitor RFS 2000; difluoromethylomithine (DMFO);retinoids such as retinoic acid; and pharmaceutically acceptable salts,acids and derivatives of any of the above.

The “chemotherapeutic agent” can also be selected, for example, from:(i) anti-hormonal agents that act to regulate or inhibit hormone actionon tumors such as anti-estrogens and selective estrogen receptormodulators (SERMs), including, for example, tamoxifen (includingNOLVADEX®; tamoxifen citrate), raloxifene, droloxifene,4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, andFARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibitthe enzyme aromatase, which regulates estrogen production in the adrenalglands, such as, for example, 4(5)-imidazoles, aminoglutethimide,MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer),formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole;Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii)anti-androgens such as flutamide, nilutamide, bicalutamide, leuprotide,and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleosidecytosine analog); (iv) protein kinase inhibitors; (v) lipid kinaseinhibitors; (vi) antisense oligonucleotides, such as those which inhibitexpression of genes in signaling pathways implicated in aberrant cellproliferation, such as, for example, PKC-alpha, Rolf and H-Ras; (vii)ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2expression inhibitors; (viii) vaccines such as gene therapy vaccines,for example. ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; atopoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; (ix)anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and(x) pharmaceutically acceptable salts, acids and derivatives of any ofthe above.

The “chemotherapeutic agent” can also be selected, for example, fromtherapeutic antibodies such as alemtuzumab (Campath), bevacizumab(AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitmumab(VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec),pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®,Genentech), tositumomab (Bexxar, Corixia), and the antibody drugconjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

Humanized monoclonal antibodies with therapeutic potential aschemotherapeutic agents in combination with a subject compound andstereoisomers thereof, and pharmaceutically acceptable salt thereof may,for example, be selected from: alemtuzumab, apolizumab, aselizumab,atlizumub, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumabmertansine, cedelizumab, certolizumab pegol, cidfusituztimab,cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab,felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin,ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab,niotavizumab, motovizumab, natalizumab, nimoiuzumab, nolovizumab,numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizuinab,pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab,ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab,ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumabtetraxetan, tadoeizumab, talizumab, tefibazumab, tocilizumab,toralizumab, trasiuzumab, tucotuzumab celmoleukin, tucusituzumab,umavizumab, urtoxazumab, and visilizumab.

Also provided is a composition comprising a subject compound andstereoisomers thereof, and pharmaceutically acceptable salts thereof,and at least one pharmaceutically acceptable carrier.

The composition comprising a subject compound and stereoisomers thereof,and pharmaceutically acceptable salts thereof can be administered invarious known manners, such as orally, topically, rectally,parenterally, by inhalation spray, or via an implanted reservoir,although the most suitable route in any given case will depend on theparticular host, and nature and severity of the conditions for which theactive ingredient is being administered. The term “parenteral” as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques. The compositions disclosed herein may beconveniently presented in unit dosage form and prepared by any of themethods well known in the art.

The subject compounds and stereoisomers thereof, and pharmaceuticallyacceptable salts thereof can be administered orally in solid dosageforms, such as capsules, tablets, troches, dragées, granules andpowders, or in liquid dosage forms, such as elixirs, syrups, emulsions,dispersions, and suspensions. The subject compounds and stereoisomersthereof, and pharmaceutically acceptable salts thereof disclosed hereincan also be administered parenterally, in sterile liquid dosage forms,such as dispersions, suspensions or solutions. Other dosages forms thatcan also be used to administer the subject compounds and stereoisomersthereof, and pharmaceutically acceptable salts thereof disclosed hereinas an ointment, cream, drops, transdermal patch or powder for topicaladministration, as an ophthalmic solution or suspension formation, i.e.,eye drops, for ocular administration, as an aerosol spray or powdercomposition for inhalation or intranasal administration, or as a cream,ointment, spray or suppository for rectal or vaginal administration.

Gelatin capsules containing the compound and/or the at least onepharmaceutically acceptable salt thereof disclosed herein and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like, can also be used. Similar diluentscan be used to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of time. Compressed tablets can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can further comprise atleast one agent selected from coloring and flavoring agents to increasepatient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene gycols can be examples of suitable carriers for parenteralsolutions. Solutions for parenteral administration may comprise a watersoluble salt of the at least one compound describe herein, at least onesuitable stabilizing agent, and if necessary, at least one buffersubstance. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, can be examples ofsuitable stabilizing agents. Citric acid and its salts and sodium EDTAcan also be used as examples of suitable stabilizing agents. Inaddition, parenteral solutions can further comprise at least onepreservative, selected, for example, from benzalkonium chloride, methyl-and propylparaben, and chlorobutanol.

A pharmaceutically acceptable carrier is, for example, selected fromcarriers that are compatible with active ingredients of the composition(and in some embodiments, capable of stabilizing the active ingredients)and not deleterious to the subject to be treated. For example,solubilizing agents, such as cyclodextrins (which can form specific,more soluble complexes with the at least one compound and/or at leastone pharmaceutically acceptable salt disclosed herein), can be utilizedas pharmaceutical excipients for delivery of the active ingredients.Examples of other carriers include colloidal silicon dioxide, magnesiumstearate, cellulose, sodium lauryl sulfate, and pigments such as D&CYellow #10. Suitable pharmaceutical acceptable carriers are described inRemington's Pharmaceutical Sciences, A. Osol, a standard reference textin the art.

The subject compounds and stereoisomers thereof, and pharmaceuticallyacceptable salts thereof disclosed herein can further be examined forefficacy in treating Btk related diseases by in vivo assays. Forexample, the compound and/or the at least one pharmaceuticallyacceptable salts thereof disclosed herein can be administered to ananimal (e.g., a mouse model) having Blk related diseases and itstherapeutic effects can be accessed. Positive results in one or more ofsuch tests are sufficient to increase the scientific storehouse ofknowledge and hence sufficient to demonstrate practical utility of thecompounds and/or salts tested. Based on the results, an appropriatedosage range and administration route for animals, such as humans, canalso be determined.

For administration by inhalation, the subject compounds andstereoisomers thereof, and pharmaceutically acceptable salts thereof maybe conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulisers. The subject compounds andstereoisomers thereof, and pharmaceutically acceptable salts thereof mayalso bet delivered as powders, which may be formulated and the powdercomposition may be inhaled with the aid of an insufflation powderinhaler device. One exemplary delivery system for inhalation can bemetered dose inhalation (MDI) aerosol, which may be formulated as asuspension or solution of a subject compound and stereoisomers thereof,and pharmaceutically acceptable salts thereof disclosed herein in atleast one suitable propellant, selected, for example, from fluorocarbonsand hydrocarbons.

For ocular administration, an ophthalmic preparation may be formulatedwith an appropriate weight percentage of a solution or suspension of thesubject compound and stereoisomers thereof, and pharmaceuticallyacceptable salts thereof in an appropriate ophthalmic vehicle, such thatthe subject compound and stereoisomers thereof, and at least onepharmaceutically acceptable salts thereof is maintained in contact withthe ocular surface for a sufficient time period to allow the compound topenetrate the corneal and internal regions of the eye.

Useful pharmaceutical dosage-forms for administration of the subjectcompounds and stereoisomers thereof, and pharmaceutically acceptablesalts thereof disclosed herein include, but are not limited to, hard andsoft gelatin capsules, tablets, parenteral injectables, and oralsuspensions.

The dosage administered will be dependent on factors, such as the age,health and weight of the recipient, the extent of disease, type ofconcurrent treatment, if any, frequency of treatment, and the nature ofthe effect desired. In general, a daily dosage of the active ingredientcan vary, for example, from 0.1 to 2000 milligrams per day. For example,10-500 milligrams once or multiple times per day may be effective toobtain the desired results.

In some embodiments, a large number of unit capsules can be prepared byfilling standard two-piece hard gelatin capsules each with, for example,100 milligrams of the subject compound and stereoisomers thereof, andpharmaceutically acceptable salt thereof disclosed herein in powder, 150milligrams of lactose, 50 milligrams of cellulose, and 6 milligramsmagnesium stearate.

In some embodiments, a mixture of the compound, stereoisomers thereof,and pharmaceutically acceptable salts thereof a digestible oil such assoybean oil, cottonseed oil or olive oil can be prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100 milligrams of the active ingredient. Thecapsules are washed and dried.

In some embodiments, a large number of tablets can be prepared byconventional procedures so that the dosage unit comprises, for example,100 milligrams of the compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof. 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmacrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

In some embodiments, a parenteral composition suitable foradministration by injection can be prepared by stirring 1.5% by weightof the compound and/or at least an enantiomer, a diastereomer, orpharmaceutically acceptable salt thereof disclosed herein in 10% byvolume propylene glycol. The solution is made to the expected volumewith water for injection and sterilized.

In some embodiment, an aqueous suspension can be prepared for oraladministration. For example, each 5 milliliters of an aqueous suspensioncomprising 100 milligrams of finely divided compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof, 100 milligramsof sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0grams of sorbitol solution. U.S.P., and 0.025 milliliters of vanillincan be used.

The same dosage forms can generally be used when the compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof areadministered stepwise or in conjunction with at least one othertherapeutic agent. When drugs are administered in physical combination,the dosage form and administration route should be selected depending onthe compatibility of the combined drugs. Thus the term coadministrationis understood to include the administration of at least two agentsconcomitantly or sequentially, or alternatively as a fixed dosecombination of the at least two active components.

The compounds, stereoisomers thereof, and pharmaceutically acceptablesalt thereof disclosed herein can be administered as the sole activeingredient or in combination with at least one second active ingredient,selected, for example, from other active ingredients known to be usefulfor treating Btk related diseases in a patient.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein, including citations therein, are herebyincorporated by reference in their entirety for all purposes,

General Reaction Scheme for Compound Preparation

The subject compounds and pharmaceutically acceptable salts thereof, canbe prepared from (a) commercially available starting materials (b) knownstarting materials which may be prepared as described in literatureprocedures (c) new intermediates described in the schemes andexperimental procedures herein. In making the compounds of theinvention, the order of synthetic steps may be varied to increase theyield of desired product. Some of compounds in this invention may begenerated by the methods as shown in the following reaction schemes andthe description thereof.

Scheme I above shows a general synthetic route that is used forpreparing the compound S-6 of this invention, where A, R₁, R₂, R₄, R₆, Land n are as described herein. Reaction of methyl ketone S-1 in acetalsof N,N-dialkylformamides or acetals of N,N-dialkylacetamide at refluxtemperature for several hours afforded 3-dialkylamino-1-(aryl,heteroaryl or alkyl)-2-propen-1-one S-2. Intermediate S-3 may beprepared by methods substantially similar to those described inInternational Patent Publication No. WO 2001/019829 and No. WO2011/046964. The reaction of intermediate S-3 and an appropriatelysubstituted 3-dialkylamino-1-(aryl, heteroaryl or alkyl)-2-propen-1-oneS-2 in weak acid such as acetic acid or in an inert solvent such astoluene, acetonitrile or dimethoxyethane with catalytic acid, at 80° C.to reflux temperature for several hours afforded the nitrile compoundS-4. Reduction of the pyrimidine ring with reducing agents such assodium borohydride (NaBH₄), Pd/C or NaBH₄ followed with Pd/C gavetetrahydropyrazolopyrimidine S-5, and subsequent hydrolysis of nitrileunder alkaline condition such as NaOH or KOH plus H₂O₂ in alcohol, orunder acid condition such as H₃PO₄, H₂SO₄, or BF₃-HOAc, yielded thecarboxamide S-6.

Scheme II describes a general synthetic route to prepare carboxamideS-13, where A, R₁, R₂, R₄, R₅, L, n and p are as described herein. Theprotected hydrazine S-7 known can be conveniently prepared by themethods as described in the literature (J. Med. Chem. 1992, 35, 2392).Deprotection with acid, followed by condensation of this building blockwith intermediate S-10 (also described in International PatentPublication No. WO 2001/019829 and No. WO 2011/046964) in alkalinesolvent such as TEA/ethanol afforded pyrazole ester S-9. The pyrazolealcohol S-11 can be prepared from an ester S-9 through a reductiveprocess. The reducing agents which may be used for this process include,but are not limited to LiBH₄, NaBH₄ and Super Hydride. IntramolecularN-alkylation or reductive amination gave the nitrites S-12, which wasconverted to carboxamide S-13 by the same methods as described in Scheme1.

Scheme III describes alternative routes to prepare carboxamide S-13.

Scheme IV above shows general synthetic routes that have been used forpreparing compounds S-19 and S-20 of this invention, where A, R₁, R₂,R₄, R₆, L and n are as described herein. Hydrolysis of nitrile S-3afforded carboxomide S-18 by the same methods as described in Scheme I.The cyclization of pyrazole carboxamide S-18 or pyrazole nitrile S-3with the commercially available or prepared haloketone S-23 gaveregioisomers S-19 and S-20, or S-21 and S-22. The nitriles S-21 and S-22were hydrolyzed to afford carboxamides S-19 and S-20 according to SchemeI.

Scheme V above shows general synthetic routes that have been used forpreparing compound S-27 of this invention, where A, R₁, R₂, R₄, R₆, L, mand n are as described herein; The pyrazole S-25 was prepared bycyclization of intermediate S-10 with the commercially available orprepared hydrazine S-24 in alcohol according to one of steps in SchemeII. The intramolecular cyclization of intermediate S-25 was performedwith the process included, but not limited to Cu catalytic coupling,Buchwald reaction, SN2 reaction or reductive amination. Finally, nitrileS-26 was hydrolyzed to afford carboxamide S-27 according to Scheme I.Alternatively, nucleophilic substitution, followed by intramolecularcyclization afforded carboxamide S-27.

Scheme VI above shows a general synthetic route that has been used forpreparing compound S-30 of this invention, where A, R₁, R₂, R₄, R₆, L, mand n are as described herein. The intramolecular amide S-30 wasprepared by heating the mixture of nitrile S-3 or carboxamide S-18 andester S-29 in inert solvent such as DMF with presence of base such asK₂CO₃ and TEA.

Scheme VII above shows a general synthetic route that has been used forpreparing compound S-32 of this invention, where A, R₁, R₂, R₄, R₆, Land n are as described herein. The amide S-32 was prepared by heatingthe mixture of nitrile S-3 or carboxamide S-18 and β-ketoester S-31 inweak acid such as acetic acid or in an inert solvent such as toluene,acetonitrile or dimethoxyethane with catalytic acid.

Scheme VIII above shows a general synthetic route that has been used forpreparing compound S-36 of this invention, when A, R₁, R₂, R₄, R₆, L, W,m and n are as described herein. The intermolecular cyclization ofnitrile S-3 or carboxamide S-18 and commercially available or preparedintermediate S-33 was performed in inert solvent such as DMF withpresence of base such as K₂CO₃ and TEA to afford compound S-36.Alternatively, condensation of nitrile S-3 or carboxamide S-18 withdialdehyde S-34, followed by reduction yielded compound S-36.

EXAMPLES

The examples below are intended to be purely exemplary and should not beconsidered to be limiting in any way. Efforts have been made to ensureaccuracy with respect to numbers used (for example, amounts,temperature, etc.), but some experimental errors and deviations shouldbe accounted for. Unless indicated otherwise, temperature is in degreesCentigrade. Reagents were purchased from commercial suppliers such asSigma-Aldrich, Alfa Aesar, or TCI, and were used without furtherpurification unless indicated otherwise.

Unless indicated otherwise, the reactions set forth below were performedunder a positive pressure of nitrogen or argon or with a drying tube inanhydrous solvents: the reaction flasks were fitted with rubber septafor the introduction of substrates and reagents via syringe; andglassware was oven dried and/or heat dried.

¹H NMR spectra were recorded on a Agilent instrument operating at 400MHz. ¹HNMR spectra were obtained using CDCl₃, CD₂Cl₂, CD₃OD, D₂O,d₆-DMSO, d₆-acetone or (CD₃)₂CO as solvent and tetramethylsilane (0.00ppm) or residual solvent (CDCl₃; 7.25 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79ppm; d₆-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD₃)₂CO: 2.05) as thereference standard. When peak multiplicities are reported, the followingabbreviations are used: s (singlet), d (doublet), t (triplet), q(quartet), qn (quintuplet), sx (sextuplet), m (multiplet), br(broadened), dd (doublet of doublets), dt (doublet of triplets).Coupling constants, when given, are reported in Hertz (Hz).

LC-MS spectrometer (Agilent 1260) Detector MWD (190-400 nm). Massdetector: 6120 SQ

-   Mobile phase: A: acetonitrile with 0.1% Formic acid, B: water with    0.1 % Formic acid-   Column: Poroshell 120 EC-C18, 4.6×50 mm, 2.7 μm-   Gradient method: Flow: 1.8 mL/min

Time (min) A (%) B (%) 0.00 5 95 1.5 95 5 2.0 95 5 2.1 5 95 3.0 5 95

Preparative HPLC was conducted on a column (150×21.2 mm ID, 5 μm, GeminiNX-C18) at a flow rate of 20 ml/min, injection volume 2 ml, at roomtemperature and UV Detection at 214 nm and 254 nm.

In the following examples, the abbreviations below are used:

-   Brine Saturated aqueous sodium chloride solution-   BnNHs Benzyl amine-   CbzCl Benzyl chloroformate-   DCM Dichloromethane-   DCE 1,2-Dichlorethane-   DIEA N,N-diisopropylethylamine-   DMF N,N-Dimethylformamide-   DMF-DMA N,N-dimethylformamidedimethylacetal-   DMAP N,N-dimethylpyridin-4-amine-   DCC N,N-dicyclohexylcarbodiimidc-   DHP 3,4-Dihydro-2H-pyrane-   EA Ethyl acetate-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOAc Acetic acid-   H₂O₂ Hydrogen peroxide solution 30% (w/w) in H₂O-   IPA Isopropanol-   MTBE Methyl tert-butyl ether-   MsCl Methanesulfuryl chloride-   NBS N-Bromosuccinimide-   Pd/C Palladium on carbon powder-   Pd(OH)₂/C Palladium hydroxide on carbon powder-   PE Petroleum ether-   PPh₃ Triphenylphosphine-   Pre-TLC Prepared thin layer chromatography-   sat. Saturated-   Tf₂O Trifluoromethanesulfonic anhydride-   THF Tetrahydrofuran-   TEA Triethylamine-   TMSCHN₂ (Trimethylsilyl)diazomethane-   TMSCl Chlorotrimethylsilane

Example 1 Synthesis of Compounds 1-4 Compound 1:7-(3-Aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Step 1: 2-(Hydroxy(4-phenoxyphenyl)methylene)malononitrile

A solution of 4-phenoxybenzoic acid (300 g, 1.4 mol) in SOCl₂ (1.2 L)was stirred al 80° C. under N₂ for 3 hr. The mixture was concentrated invacuum to give the intermediate (315 g) which was used for next stepwithout further purification.

To a solution of propanedinitrile (89.5 g, 1355 mmol) and DIEA (350 g,2710 mmol) in THF (800 mL) was dropwise a solution of the intermediate(315 g) in toluene (800 mL) at 0˜5+ C. over 2 hr. The resultant mixturewas allowed to warm to RT and stirred for 16 hr. The reaction wasquenched with water (2.0 L) and extracted with of EA (2.0 L×3). Thecombined organic layers were washed with 1000 mL of 3 N HCl aqueoussolution, brine (2.0 L×3), dried over Na₂SO₄ and concentrated to givethe crude product (330 g, 93%). ¹H NMR (DMSO-d₆) δ7.62 (d, J=8.8 Hz,2H), 7.46-7.38 (m, 2H). 7.18 (t. J=7.6 Hz. 1H). 7.06 (d, J=8.0 Hz, 2H),6.94 (d, J=8.8 Hz, 2H). MS (ESI) m/e [M+1]⁺ 262.9.

Step 2: 2-(Methoxy(4-phenoxyphenyl)methylene)malononitrile

A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g,190.8 mmol) in CH(OMe)₃ (500 mL) was heated to 75° C. for 16 hr. Thenthe mixture was concentrated to a residue and washed with MeOH (50 mL)to give 25 g (47.5%) of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile as a yellow solid. ¹H NMR (DMSO-₆) δ7.70 (d,J=8.4 Hz, 2H), 7.52-7.45 (m, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.22-7.06 (m,4H), 3.93 (s, 3H). MS (ESI) m/e [M+1]⁺ 276.9.

Step 3: 5-Amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile

To a solution of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (80g, 290 mmol) in ethanol (200 mL) was added hydrazine hydrate (20 mL).The mixture was stirred at RT for 16 hr then was concentrated to givethe crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile us a off-whitesolid. ¹H NMR (DMSO-d₆) δ 12.11 (br s, 1H), 7.80 (d, J=8.8 Hz, 2H),7.46-7.39 (m, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.12-7.04 (m, 4H), 6.43 (brs, 2H).

Step 4: (E)-N-(3-(3-(dimethylamino)acryloyl)phenyl)acetamide

A solution of N-(3-acetylphenyl)acetamide (1.77 g, 10.0 mmol) in DMF-DMA(6 mL) with molecular sieve (10 portions) was stirred at 100° C. underN2 for 2 hr. the mixture was concentrated and washed with MTBE (30 mL)to afford 2.1 g (90%) of (E)-N-(3-(3-(dimethylamino)acryloyl)phenyl)acetamide as a yellow solid.

Step 5:N-(3-(3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)acetamide

To a solution of (E)-N-(3-(3-(dimethylamino)acryloyl)phenyl)acetamide(46 mg, 0.2 mmol) in HOAc (5 mL) was added5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (55 mg, 0.2mmol). The mixture was stirred at 118° C. for 4 hr. Then the reactionmixture was concentrated to a residue and partitioned between ethylacetate (100 mL) and brine (100 mL), Organic layer was separated, washedwith brine (2×100 mL), dried over sodium sulfate and concentrated toafford 80 mg (90%) ofN-(3-(3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)acetamide as a colorless oil. MS (ESI) m/e [M+1]⁺ 446.

Step 6:7-(3-Aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution ofN-(3-(3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)acetamide (285 mg, 0.64 mmol) in ethanol (6 mL) was added HCl (3mL). The mixture stirred at 75° C. for 3 hr. Concentrated to afford 250mg (97%) of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. ¹H NMR (400MHz, DMSQ-d₆) δ 8.90 (d, J=4.4 Hz, 1H), 8.67 (br s, 2H), 8.15 (d, J=8.8Hz, 2H), 8.06 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H),7.57 (d, J=4.4 Hz, 1H). 7.48-7.44 (m, 3H), 7.25-7.18 (m, 3H), 7.13 (d,J=8.0 Hz, 2H). MS (ESI) m/e [M+1]⁺ 404.

Compound 2:7-(3-Aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: 7-(3-Aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile(150 mg, 0.372 mmol) in ethanol (10 mL) was added NaBH4 (70 mg, 1.86mmol). The mixture was stirred at rt for 16 hr and 60° C. for 2 hr. Thenthe reaction mixture was concentrated to a residue and partitionedbetween EA (50 mL) and brine (40 mL). Organic layer was separated fromaqueous layer, washed with brine (50 mL×2), dried over Na₂SO₄ andconcentrated to afford 135 mg (crude) of7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. MS (ESI) m/e [M+1]⁺408.

Step 2:7-(3-Aminophenyl)-2-(4-phenoxyphenyl)4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (130 mg, 0,32 mmol) in DMSO (2mL) and ethanol (2 mL) was added a solution of 5 N NaOH aqueous solution(1 mL) and H₂O₂ (1 mL). The mixture was stirred at 60° C. for 30minutes, concentrated and partitioned between EA (100 mL) and brine (100mL). Organic layer was separated, washed with brine (3×100 mL), driedover Na₂SO₄ and purified by cinematography column on silica gel elutingwith PE/EA to afford 35 mg (26%) of7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (d, J=8.4 Hz, 2H),7.40-7.33 (m, 2H), 7.16 (t, J=7.6 Hz, 1H), 7.06 (d, J=8.0 Hz, 2H), 7.03(d, J=8.4 Hzt 2H), 6.97 (t, J=7.6 Hz, 1H), 6.76 (s, 1H), 6.44 (d, J=8.4Hz, 1H), 6.23-6.21 (m, 2H), 5.30-5.25 (m, 1H), 5.09 (s, 2H), 3.30-3.28(m, 1H), 3.12-3.02 (m, 1H), 2.34-2.26 (m, 1H), 2.05-2.01 (m, 1H). MS(ESI) m/e [M+1]⁺ 426.

Compound 2 was separated into two enantiomeric stereoisomers compound 2a(peak 1, R or S, retention time at 8.94 min in chiral analysis), andcompound 2b (peak 2, S or R, retention time at 10.11 min in chiralanalysts) by chiral prep-HPLC. The chiral separation conditions areshown below.

Column CHIRALCEL AS-H Column size 2 cm × 25 cm Injection 2 mL Mobilephase CO₂/MeOH = 70/30 Flow rate 45 mL/min Wave length UV 210 nmTemperature 35° C. Sample solution 6 mg/mL in mobile phase Prep-SFCequipment DAICEL-SFC

The chiral analysis conditions are shown below.

Column CHIRALPAK AD-H Column size 0.46 cm I.D. × 15 cm L, 5 um Injection2 uL Mobile phase n-Hexane/EtOH (0.1% triethyl amine) = 50/50 (v/v) Flowrate 1.0 mL/min Wave length UV 214, 254 nm

Compound 3 and 4:7-(3-Acrylamidophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and7-(3-(3-chloropropanamido)phenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.071 mmol) in DCM (2mL) was added pyridine (0.2 mL). Then acryloyl chloride (6 mg, 0.084mmol) was added dropwise. The mixture was stirred at RT for 0.5 hr andpartitioned between DCM (20 mL) and brine (20 mL). Organic layer wasseparated from aqueous layer, washed with brine (2×20 mL), dried overNa₂SO₄ and purified by Pre-TLC (DCM/CH₃OH=10/1) to afford 1.82 mg(5.38%) of7-(3-acrylamidophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. ¹H NMR (400 MHz,CD₃OD) δ 7.58 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.34-7.26 (m,4H), 7.10 (t, J=7.6 Hz, 1H), 7.04-6.95 (m, 4H), 6.84 (d, J=7.6 Hz, 1H),6.39-6.25 (m, 2H), 5.69 (dd, J=2.4, 9.6 Hz, 1H), 5.47-5.44 (m, 1H),3.38-3.31 (m, 1H), 3.22-3.12 (m, 1H), 2.52-2.42 (m, 1H), 2.23-2.17 (m,1H). MS (ESI) m/e [M+1]⁺ 480.

2.21 mg of byproduct7-(3-(3-chloropropanamido)phenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidine-3-carboxamide as a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.8Hz, 2H), 7.42-7.30 (m, 4H), 7.16 (t, J=7.6 Hz, 1H).7.09-7.01 (m, 4H),6.89 (d, J=8.0 Hz, 1H), 5.53-5.48 (m, 1H), 3.85 (t, J=6.4 Hz, 2H),3.44-3.37 (m, 1H), 3.26-3.19 (m, 1H), 2.83 (t, J=6.4 Hz, 2H), 2.60-2.44(m, 1H), 2.33-2.22 (m, 1H). MS (ESI) m/e [M+1]⁺ 516.2.

Compound 3a (peak 1, R or S, retention lime at 4.45 min) and 3b (peak 2,R or S, retention time at 7.41 min) was prepared from 2a and 2baccording to the procedure similar to those for compound 3.

The chiral analysis conditions are shown below.

Column CHIRALPAK AD-H Column size 0.46 cm I.D. × 15 cm L, 5 um Injection2 uL Mobile phase n-Hexane/EtOH (0.1% triethyl amine) = 50/50 (v/v) Flowrate 1.0 mL/min Wave length UV 254 nm

Compound 5:7-(2-Aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from 1-(2-nitrophenyl)ethanone and5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile according to theprocedures similar to those for 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (step 4 to step 5), compound 2(step 1 and 2) and compound 68 (step 8) under appropriate conditionsrecognized by one of ordinary skill in the art. ¹H NMR (DMSO-d₆) δ7.48-7.44 (m, 2H). 7.40-7.33 (m, 2H), 7.15-7.09 (m, 1H), 7.05-6.97 (m,4H), 6.92 (td, J=8.0, 1.2 Hz, 1H), 6.75 (br s, 1H), 6.64 (dd, J=8.0, 1.2Hz, 1H), 6.46 (td, J=7.6, 1.2 Hz, 1H), 6.23 (dd, J=7.6, 1.2 Hz, 1H),5.57-5.52 (m, 1H), 5.19 (br s, 2H), 3.27-3.17 (m, 1H), 2.93 (td, J=2.8,12.0 Hz, 1H), 2.21-2.11 (m, 1H), 2.10-2.05 (m, 1H). MS (ESI) m/e [M+1]⁺426.0.

Compound 5 was separated into two enantiomeric stereoisomers compound 5a(peak 1, R or S, retention time at 7.30 min in chiral analysis), andcompound 5b (peak 2, S or R, retention time at 9.68 min in chiralanalysis) by chiral prep-HPLC. The chiral separation conditions areshown below.

Column CHIRALCEL OD-H Column size 3 cm × 25 cm Injection 8 mL Mobilephase Hexane/IPA = 50/50 Flow rate 20 mL/min Wave length UV 254 nmTemperature 35 □ Sample solution 4 mg/mL in mobile phase Prep-SFCequipment DAICEL-YMC

The chiral analysis conditions are shown below.

Column CHIRALPAK IC Column size 0.46 cm I.D. × 15 cm L Injection 2 uLMobile phase MeOH = 100 (v/v) Flow rate 1.0 mL/min Wave length UV 254 nm

Compound 6:7-(2-Acrylamidophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired compound was prepared from compounds and acryloyl chlorideaccording to the procedure similar to that for compound 3. ¹H NMR(DMSO-d₆) δ 9.81 (s, 1H), 7.50-7.32 (m, 5H), 7.26 (td, J=7.6, 1.2 Hz,1H), 7.21-7.08 (m, 2H), 7.04-6.98 (m, 4H), 6.79 (s, 1H), 6.60 (dd,J=7.6, 1.2 Hz, 1H), 6.50 (dd, J=17.0, 10.2 Hz, 1H), 6.24 (dd, J=17.0,1.9 Hz, 1H), 5.77-5.74 (m, 2H), 3.26-3.22 (m, 1H), 2.98-2.92 (m, 1H),2.32-2.25 (m, 1H), 1.96-1.93 (m, 1H). MS (ESI) m/e [M+1]⁺ 480.

Compound 6a (peak 1, R or S, retention time at 4.02 min) and 6b (peak 2,R or S, retention time at 6.68 min) was prepared from 5a and 5baccording to the procedure similar to that for compound 3.

The chiral analysis conditions are shown below.

Column CHIRALPAK AD-H Column size 0.46 cm I.D. × 15 cm L, 5 um Injection2 uL Mobile phase n-Hexane/EtOH (0.1% triethyl amine) = 70/30 (v/v) Flowrate 1.0 mL/min Wave length UV 214, 254 nm

Example 2 Synthesis of Compounds 7 and 8 Compound:7-(3-Aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (4 mg, 0.01 mmol) in DCE (2 mL)was added active MnO₂ (100 mg, 1.15 mmol). The mixture was stirred at75° C. for 2 hr and filtered. The filtrate was purified by Pre-TLC(DCM/CH₃OH=10/1) to afford 2 mg (50%) of7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. ¹H NMR (400MHz, CD₃OD-d₄ and CDCl₃-d₁) δ 8.62 (d, J=4.4 Hz, 1H), 7.88 (d, J=8.8 Hz,2H), 7.41-7.39 (m, 2H), 7.31 -7.26 (m, 3H), 7.11 (d, J=4.4 Hz, 1H),7.10-7.04 (m, 1H), 7.01 -6.97 (m, 4H), 6.90-6.86 (m, 1H).

Compound 8:7-(3-Acrylamidophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.24 mmol) in DCM (10 mL) was added TEA (3 drops), followed byacryloyl chloride (32 mg, 0.36 mmol). The mixture was stirred at RT for1 min and partitioned between DCM (50 mL) and brine (50 mL). Organiclayer was separated from aqueous layer, dried over Na₂SO₄, concentratedand purified by Pre-TLC (DCM/CH₃OH=10/1) to afford 12 mg (11%) of7-(3-acrylamidophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamideas a white solid. 1H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 8.80 (d,J=4.4 Hz, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.89(d, J=8.4 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.56 (t, 7=8.0 Hz, 1H), 7.47(br s, 1H), 7.42-7.37 (m, 3H), 7.15 (t, 7=7.6 Hz, 1H), 7.06 (d, J=8.0Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.44 (dd, J=10.1, 16.9 Hz, 1H), 6.26(dd, J=1.6, 16.9 Hz, 1H), 5.76 (dd, J=1.6, 10.1 Hz, 1H). MS (ESI) m/e[M+1]⁺ 476.

Example 3 Synthesis of Compounds 9-10 Compound 9:7-(2-Aminophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1,2,3: 5-Amino-3-(4-(benzyloxy)phenyl)-1H-pyrazole-4-carbonitrile

The desired product was prepared from 4-(benzyloxy)benzoic acidaccording to the procedures similar to those (step 1 to 3) for5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile under appropriateconditions recognized by one of ordinary skill in the art. ¹H NMR (400MHz, DMSO-d₆) δ 12.01 (s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.50-7.44 (m,2H), 7.44-7.37 (m, 2H), 7.36-7.32 (m, 1H), 7.11 (d, J=7.2 Hz, 2H). 6.39(br s, 2H) and 5.16 (s, 2H).

Step 4,5:2-(4-(Benzyloxy)phenyl)-7-(2-nitrophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

The desired product was prepared from 1-(2-nitrophenyl)ethanone and5-amino-3-(4-(benzyloxy) phenyl)-1H-pyrazole-4-carbonitrile according tothe procedures similar to those (step 4 and step 5) forN-(3-(3-cyano-2-(4-phenoxyphenyl) pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)acetamide under appropriate conditions recognized by one ofordinary skill in the art.

Step 6: 7-(2-Aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of2-(4-(benzyloxy)phenyl)-7-(2-nitrophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile(2 g, 4.47 mmol) in CH₃OH (20 mL) and DCM (20 mL) was added 10% w/w Pd/C(300 mg). The mixture was stirred at RT under H; for 16 hr. Filtered andpurified by chromatography column on silica gel (elution with DGM/CH₃OH)to afford 0.92 g (62%) of7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. MS (ESI, m/e) [M+1]⁺331.9.

Step 7:7-(2-Aminophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (331 mg, 1.0 mmol) in acetone(10 mL) was added (bromomethyl)benzene (204 mg, 1.2 mmol) and K₂CO₃ (276mg, 2.0 mmol). The mixture was stirred at RT for 16 hr. 50 mL of acetonewas added and filtered. The filtrate was concentrated to afford 400 mg(95%) of7-(2-aminophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. MS (ESI) m/e [M+1]⁺421.9.

Step 8:7-(2-Aminophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from7-(2-aminophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2for compound 2. NMR (400 MHz, DMSO-d₆) δ 7.47-7.33 (m, 7H), 7.06 (d,J=8.4 Hz, 2H), 6.96 (t, J=1.6 Hz, 1H), 6.75 (br s, 1H), 6.68 (d, J=7.6Hz, 1H), 6.50 (t, J=7.6 Hz, 1H), 6.28 (d, J=7.6 Hz, 1H), 5.59-5.54 (m,1H), 5.19 (br s,2H), 5.12 (s, 2H), 3.30-3.20(m, 1H), 3.02-2.92 (m, 1H).2.25-2.14 (m, 1H) and2.13-2.03 (m, 1H), MS (ESI) m/e [M+1]⁺ 439.9.

Compound 10:7-(2-Acrylamidophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from7-(2-aminophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and acryloyl chloride using theprocedure similar to that for compound 8. ¹H NMR (400 MHz, DMSO-d₆) δ9.84 (s, 1H), 7.46-7.37 (m, 7H), 7.33-7.28 (m, 2H), 7.21 (t, J=7.6 Hz,1H), 7.06 (d, J=8.8 Hz, 2H), 6.81 (br s, 1H), 6.64 (d, J=7.6 Hz, 1H),6.53 (dd, J=10.3, 16.8 Hz, 1H), 6.27 (d, J=1.8, 16.8 Hz, 1H), 5.59-5.57(m, 2H), 5.12 (s, 2H), 3.30-3.26 (m, 1H), 3.04-2.92 (m, 1H), 2.35-2.27(m, 1H) and 1.95-1.97 (m, 1H). MS (ESI) m/e [M+1]⁺ 493.9.

Compound 10 was separated into two enantiomeric stereoisomers compound10a (peak 1, R or S, retention time at 3.15 min in chiral analysis), andcompound 10b (peak 2, S or R. retention time at 3.91 min in chiralanalysis) by chiral prep-HPLC. The chiral separation conditions areshown below.

Column CHIRALPAK IC-3 Column size 2 cm × 25 cm Injection 3 mL Mobilephase MeOH/ACN = 50/50 Flow rate 10 mL/min Wave length UV 220 nmTemperature 35 □ Sample solution 2.5 mg/mL in mobile phase Prep-SFCequipment DAICEL-YMC

The chiral analysis conditions are shown below.

Column CHIRALPAK IC Column size 0.46 cm I.D. × 15 cm L, 5 um Injection 3uL Mobile phase MeOH/ACN = 50/50 (v/v) Flow rate 1.0 mL/min Wave lengthUV 214, 254 nm

Example 4 Synthesis of Compounds 11-12 Compound 11:7-(2-Aminophenyl)-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Benzyl2-(3-cyano-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate

To a solution of7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (730 mg, 2.21 mmol) in THF (30mL) was added K₂CO₃ (610 mg, 4.42 mmol), CbzCl (564 mg, 3.32 mmol).After stirring at 65° C. for 16 hr, the mixture was concentrated invacuum. The residue was partitioned between 150 mL of DCM and 150 mL ofbrine. Organic layers were separated from aqueous layers, dried overNa₂SO₄ and purified by chromatography column on silica gel eluting withDCM/CH₃OH to afford 370 mg (62%) of benzyl2-(3-cyano-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.71 (s,1H), 9.33 (s, 1H), 7.66 (s, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.44-7.28 (m,7H), 7.17 (t, J=7.6 Hz, 1H), 6.79 (d, J=8.4 Hz, 2H), 6.59 (d, J=7.6 Hz,1H), 5.82-5.77 (m, 1H), 5.17 (s, 2H), 3.25-3.18 (m, 1H), 2.97-2.87 (m,1H), 2.36-2.24 (m, 1H), 2.08-2.00 (m, 1H).

Step 2: Benzyl2-(3-cyano-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate

To a solution of benzyl 2-(3-cyano-2(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate (370 mg, 0.8 mmol) in 20mL of DCM was added 4-fluorophenylboronic acid (167 mg, 1.2 mmol), TEA(162 mg, 1.6 mmol) and Cu(OAc)₂ (216 mg, 1.2 mmol). After stirring at RTfor 16 hr, 100 mL of DCM, 10 mL of CH₃OH and 100 mL of brine were addedto the mixture. Organic layers were separated from aqueous layers,washed with brine (100 mL×2), dried over Na₂SO₄ and purified bychromatography column on silica gel eluting with DCM/CH₃OH to afford 334mg (75%) of benzyl 2-(3-cyano-2-(4-(4-fluorophenoxy) phenyl)4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate as awhite solid. ¹H NMR (400 MHz, DMSQ-d₆) δ 9.34 (s, 1H), 7.76-7.74 (m,3H), 7.45-7.10 (m, 12H), 7.02 (d, J=8.4 Hz, 2H), 6.59 (d, J=8.0 Hz, 1H),5.85-5.80 (m, 1H), 5.17 (s, 2H), 3.25-3.18 (m, 1H), 2.97-2.87 (m, 1H),2.36-2.24 (m, 1H), 2.08-2.00 (m, 1H).

Step 3: Benzyl2-(3-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate

The desired product was prepared from benzyl2-(3-cyano-2-(4-(4-fluorophenoxy) phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate using the procedure similar tostep 2 for compound 2. MS (ESI) m/e [M+1]⁺ 577.9.

Step 4:7-(2-Aminophenyl)-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of benzyl2-(3-carbamoyl-2-(4-(4-fluorphenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate (100 mg, 0.17 mmol) in 5 mL of DCMand 5 mL of CH₃OH was added 10% w/w Pd/C (50 mg). After stirring at RTunder H₂ for 16 hr, the mixture was filtered and the cake was washedwith DCM/CH₃OH (1/1, 50 mL). The filtrate was concentrated and purifiedby chromatography column on silica gel eluting with DCM/CH3OH to afford10 mg (13%) of7-(2-aminophenyl)-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. ¹H NMR (400 MHz,CD₃OD-d₄) δ 7.39 (d, J=8.8 Hz, 2H), 7.02-6.91 (m, 7H), 6.66 (d, J=7.6Hz, 1H), 6.53 (t, J=7.6 Hz, 1H), 6.33 (d, J=7.6 Hz, 1H), 5.54-5.50 (m,1H), 3.30-3.24 (m, 1H), 3.12-3.06 (m, 1H) and 2,31-2.20 (m, 2H), MS(ESI) m/e [M+1]⁺ 443.9.

Compound 12:7-(2-Acrylamidophenyl)-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from7-(2-aminophenyl)-2-(4-(4-fluorophenoxy) phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and acryloyl chloride using theprocedure similar to that for compound 8. ¹H NMR (400 MHz, CD₃OD-d₄) δ7.47 (d, J=8.4 Hz, 2H), 7.39 (t, J=7.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H),7.26 (t, J=7.6 Hz, 1H), 7.12-7.00 (m, 6H), 6.81 (d, J=8.0 Hz. 1H),6.53-6.46 (m, 1H), 6.39-6.35 (m, 1H), 5.87-5.76 (m, 1H), 5.73-5.69 (m,1H), 3.36-3.30 (m, 1H), 3.22-3.17 (m, 1H), 2.45-2,39 (m, 1H) and2.17-2.14 (m, 1H). MS (ESI) m/e [M+1]⁺ 497.9.

Example 5 Synthesis of Compounds 13-14 Compound 13:7-(2-(Methylamino)phenyl)2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1:N-(2-(3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide

To a solution of7-(2-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile(60 mg, 0.15 mmol) in 5 mL of DCM was added three drops of DIEA andthree drops of trifluoroacetic anhydride. The reaction mixture wasstirred at rt for 2 hr, then partitioned between water (20 mL) and DCM(20 mL). The organic layer was concentrated to give the product as ayellow solid (50 mg, yield: 67%), which was used in the next stepwithout further purification.

Step 2:7-(2-(Methylamino)phenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution ofN-(2-(3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide (50 mg, 0.1 mmol) in 5 mL of acetonewas added KOH (11.2 mg, 0.2 mmol) and CH3I (0.5 mL). The reactionmixture was stirred at rt for 15 hr, then concentrated to removeacetone. The residue was partitioned between 20 mL of water and 20 mL ofHA. The organic layer was concentrated and purified by pre-TLC (PE/EA2/1) to give the product as a white solid (15 mg, yield: 37%). ¹H NMR(DMSO-d6) δ 8;82 (d, J=4.4 Hz. 1 H), 7.97 (d, J=8.8 Hz, 2H), 7.47-7.38(m, 4H), 7.31 (dd, J=1.6, 7.2 Hz, 1H), 7.23-7.17 (m, 3H), 7. II (d,J=8.8 Hz, 2H), 6.77-6.69 (m, 2H), 5.35-5.31 (m, 1H), 2.68 (dt, J=4.8 Hz,3H). MS (ESI) m/e [M+1]⁺ 417.9.

Step 3:7-(2-(Methylamino)phenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of7-(2-(methylamino)phenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile(250 mg, 0.6 mmol) in 10 mL EtOH was added NaBH₄ (100 mg). The reactionmixture was stirred at rt for 15 hr, and then concentrated to removeEtOH. The residue was partitioned between 30 mL of water and 30 mL ofEA. The organic layer was concentrated. The residue was dissolved in 10mL of MeOH, followed by 10% w/w Pd/C (50 mg). The reaction mixture wasstirred at rt under 1 atm, of H₂ for 15 hr. Then, the mixture wasfiltered The filtrate was concentrated and purified by the flashchromatography (PE/EA=1/1) to give the product as a white solid (144 mg,yield: 56.5%). MS (ESI) m/e [M+1]⁺ 421,9.

Step 4:7-(2-(Methylamino)phenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from7-(2-(methylamino)phenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile usingthe procedure similar to step 2 for compound 2. ¹H NMR (DMSO-d₆) δ 7.49(d, J=8.8 Hz, 2H), 7.44-7.35 (m, 2H), 7.18-7.01 (m, 6H), 6.76 (s, 1H),6.58 (d,=7.6 Hz, 2H), 6.54 (t, J=7.6 Hz, 1H), 6.28 (dd, J=1.2, 7.6Hz,1H), 5.60-5.57 (m, 1H), 5.50-5.49 (m, 1H), 3.29-3.24 (m, 1H), 2.98-2.93(m, 1H), 2.76 (d, J=4.8 Hz, 3H), 2.24-2.18 (m, 1H), 2.06-2.03 (m, 1H).MS (ESI) m/e [M+1]⁺ 439.8.

Compound 14:7-(2-(N-methylacrylamido)phenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from7-(2-(methylamino)phenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidine-3-carboxamide andacryloyl chloride using the procedure similar to that for compound 8. ¹HNMR (DMSO-d₆) δ 7.45-7.37 (m, 6H), 7.29-7.24 (m, 1H), 7.15 (t, J=7.6 Hz,1H), 7.06-7.00 (m, 5H), 6.81 (d, J=7.6 Hz, 1H), 6.25-6.16 (m, 2H),5.94-5.87 (m, 1H), 5.63-5.51 (m, 1H), 5.41-5.35 (m, 1H), 3.41-3.22 (m,5H). 2.41-1.97 (m, 2H). MS (ESI) m/e [M+1]⁺ 493.9.

Example 6 Synthesis of Compounds 15-16 Compound 15:2-(4-(4-Fluorophenoxy)phenyl)-7-(2-(methylamino)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1:N-(2-(3-cyano-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide

To a solution of7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (33.1 mg, 0.1 mmol) in DCM (10mL) was added trifluoroacetic anhydride (1 drop) and DIEA (1 drop).After stirring at RT for 1 hr, the mixture was partitioned between 10 mLof DCM and 10 mL of brine. Organic layer was separated from aqueouslayers, dried over Na₂SO₄ and concentrated to afford 40 mg (93%) ofN-(2-(3-cyano-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide as a yellowsolid. MS (ESI) m/e [M+1]⁺ 427.8.

Step 2:N-(2-(3-cyano-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide

To a solution ofN-(2-(3-cyano-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide (42.7 mg, 0.10mmol) in DCM (3 mL) was added 4-fluorophenylboronic acid (17 mg, 0.12mmol), TEA (21 mg, 0.2 mmol) and Cu(OAc)₂ (22 mg, 0.12 mmol). Afterstirring at RT for 16 hr, the mixture was purified by Pre-TLC(DCM/CH₃OH=20/1) to afford 30 mg (57%) ofN-(2-(3-cyano-2-(4-(4-fluorophenoxy)pheny)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide as a colorlessoil. ¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 7.90-7.77 (m, 3H),7.52-7.37 (m, 3H), 7.34-7.27 (m, 2H), 7.22-7.14 (m, 2H), 7.10 (d, J=8.8Hz, 2H), 6.80 (d, J=6.4 Hz, 1H), 5.80-5.75 (m, 1H), 3.37-3.28 (m, 1H),3.09-2.95 (m, 1H), 2.50-2.37 (m, 1H), 2.10-1.95 (m, 1H). MS(ESI) m/e[M+1]⁺ 521.8.

Step 3:N-(2-(3-cyano-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoro-N-methylacetamide

To a solution ofN-(2-(3-cyano-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide (187 mg,0.36 mmol) in acetone (10 mL) was added K₂CO₃ (100 mg, 0.72 mmol) andCH₃I (15 drops). After stirring at RT for 2 hr, the mixture wasfiltered. The filtrate was concentrated to afford 192 mg (100%) ofN-(2-(3-cyano-2-(4-(4-fluorophenoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoro-N-methylacetamideas yellow solid. MS (ESI) m/e [M+1]⁺ 535.8.

Step 4:2-(4-(4-Fluorophenoxy)phenyl)-7-(2-(methylamino)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared formN-(2-(3-cyano-2-(4-(4-fluorophenoxy) phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoro-N-methylacetamide usingthe procedure similar to step 2 for compound 2. ¹H NMR (400 MHz,CD₃OD-d₄) δ 7.39 (d, J=8.8 Hz, 2H), 7.09-6.90 (m, 7H), 6.58 (d, J=8.0Hz, 1H), 6.51 (t, J=7.2 Hz, 1H), 6.30 (d, J=1.2 Hz, 1H), 5.52-5.48 (m,1H), 3.27-3.24(m, 1H), 3.11-3.02 (m, 1H), 2.76 (s, 3H), 2.32-2.10 (m,2H). MS (ESI) m/e [M+1]⁺ 457.9.

Compound 16:2-(4-(4-Fluorophenoxy)phenyl)-7-(2-(N-methylacrylamido)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from2-(4-(4-fluorophenoxy)phenyl)-7-(2-(methylamino)phenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carboxamide andacryloyl chloride using the procedure similar to that for compound 8. ¹HNMR (400 MHz, DMSO-d₆) δ 7.47-7.37 (m, 4H), 7.30-7.15 (m, 3H), 7.12-7.08(m, 2H), 6.99 (d, J=8.4 Hz, 2H), 6.81 (d, J=7.2 Hz, 1H), 6.25-5.85 (m,2H), 5.63-5.49 (m, 1H), 5.42-5.32 (m, 1H), 3.40-3.20 (m, 6H), 2.45-2.20(m, 1H), 2.15-1.90 (m, 1H). MS (ESI) m/e [M+1]+ 511.9.

Example 7 Synthesis of Compounds 17-18 Compound 17:7-(2-Aminophenyl)-2-(4-(cyclopentyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6.7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile and bromocyclopentane using theprocedures similar to those (step 7 and step 8) for compound 9, underappropriate conditions recognized by one of ordinary skill in the art.¹H NMR (400 MHz, DMSO-d₆) δ 7.37 (d, J=8.8 Hz, 2H), 6.97-6.92 (m, 3H),6.74 (br s, 1H), 6.67 (d, J=7.6 Hz. 1H), 6.49 (t, J=7:6 Hz, 1H), 6.27(d, J=1.6 Hz, 1H), 5.58-5.53 (m, 1H), 5.15 (s, 2H), 4.86-4.80 (m, 1H),3.24-3.27 (m, 1H), 3.02-2.93 (m, 1H), 2.22-2.16 (m, 1H), 2.14-2.08 (m,1H), 1.98-1.85 (m,2H), 1.91-1.70(m.4H), 1.64-1.54 (m, 2H). MS (ESI) m/e[M+1]⁺ 418.0.

Compound 18:7-(2-Acrylamidophenyl)-2-(4-(cyclopentyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from compound 17 and acryloyl chlorideusing the procedure similar to that for compound 8. ¹H NMR (400 MHz,DMSO-d₆) δ 9.83 (s, 1H), 7.45 (d, J=7.6 Hz, 1H). 7.37 (d, J=8.8 Hz, 2H)7.29 (t, J=7.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 6.93 (d, J=8.8Hz, 2H),6.81 (s, 1H), 6.64 (d, J=7.6 Hz, 1H), 6.53 (dd, J=10.2, 17.0 Hz, 1H),6.27 (d, J=17.0 Hz, 1H), 5.80-5.77 (m, 2H), 4.86-4.79 (m, 1H), 3.27-3.23(m, 1H), 3.03-2.94 (m, 1H), 2,36-2.25 (m, 1H), 1.99-1.91(m, 3H) and1.75-1.53 (m, 6H). MS (ESI) m/e [M+1]⁺ 471.9.

Example 8 Synthesis of Compounds 19-20 Compound 19:7-(2-Aminophenyl)-2-(4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1:7-(2-Aminophenyl)-2-(4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile(331 mg, 1.0 mmol) in acetone (15 mL) was added(bromomethyl)cyclopropane (135 mg, 1.0 mmol) and K₂CO₃ (276 mg, 2.0mmol). After stirring at 56° C. for 16 hr, the mixture was filtered. Thecake was washed with acetone (20 mL×2). The filtrate was concentrated toafford 300 mg of desired product (78%) as n yellow solid. MS (ESI) m/e[M+1]⁺ 386.0.

Step 2:7-(2-Aminophenyl)-2-(4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of7-(2-aminophenyl)-2-(4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (350 mg, 0.91 mmol) in EtOH (4 mL) andDMSO (4 mL) was added NaOH aqueous solution (5 N, 2 mL) and H₂O₂ (2 mL).After stirring at 60° C. for 3 hr, the mixture was partitioned between100 mL of H₂O and 100 mL of EA. The organic layer was separated fromaqueous layers, washed with saturated brines (100 mL×2), dried overNa₂SO₄ and concentrated. The residue was purified by chromatographycolumn on silica gel (elution with DCM/MeOH) to afford 150 mg (41%) ofdesired product as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.37 (d,J=8.8 Hz, 2H), 6.97-6.92 (m, 3H), 6.75 (br s, 1H), 6.67 (d, J=8.0 Hz,1H), 6.49 (t, J=7.6 Hz. 1H), 6.27 (d, J=7.6 Hz, 1H), 5.58-5.54 (m, 1H),5.16 (s, 2H), 3.83 (d, J=12 Hz, 2H), 3.27-3.24 (m, 1H), 3.01-2.92 (m,1H), 2.23-2.13 (m. 1H), 2.13-2.07 (m, 1H), 1.24-1.18 (m, 1H), 0.59-0.54(m, 2H) and 0.34-0.30 (m, 2H). MS (ESI) m/e [M+1]⁺ 404.0.

Compound 20:7-(2-Acrylamidophenyl)-2-(4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from compound 19 and acryloyl chlorideaccording to the procedure similar to that for compound 8. ¹H NMR (400MHz, DMSQ-d₆) δ 9.83 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.37 (d, J=8,4 Hz,2H), 7.30 (t, J=7.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 6.96 (d, J=8.4 Hz,2H), 6.81 (s, 1H), 6.64 (d, J=8.0 Hz, 1H), 6.53 (dd, J=10.2. 16.7 Hz,1H), 6.27 (d, J=16.7 Hz, 1H), 5.80-5.77 (m, 2H), 3.83 (d, J=7.2 Hz, 2H)3.27-3.23 (m, 1H), 3.03-2.93 (m, 1H), 2,36-2.25(m, 1H), 2.02-1.91 (m,1H), 1.23-1.14 (m, 1H), 0.59-0.53 (m, 2H) and 0.34-0.29 (m, 2H). MS(ESI) m/e [M+1]⁺ 457.9.

Compound 20 was separated into two enantiomeric stereoisomers compound20a (peak 1, R or S, retention time at 3.03 min in chiral analysis), andcompound 20b (peak 2, S or R, retention time at 3.82 min in chiralanalysis) by chiral prep-HPLC. The chiral separation conditions areshown below.

Column CHIRALPAK IC-3 Column size 2 cm × 25 cm Injection 3 mL Mobilephase MeOH/ACN = 50/50 Flow rate 10 mL/min Wave length UV 254 nmTemperature 35° C. Sample solution 2.5 mg/mL in mobile phase Prep-SFCequipment DAICEL-YMC

The chiral analysis conditions are shown below.

Column CHIRALPAK IC Column size 0.46 cm I.D. × 15 cm L, 5 um Injection 3uL Mobile phase MeOH/ACN = 50/50 (v/v) Flow rate 1.0 mL/min Wave lengthUV 214, 254 nm

Example 9 Synthesis of Compounds 21-22 Compound 21:7-(2-Aminophenyl)-2-(4-(2-methoxyethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile and 1-bromo-2-methoxyethane using theprocedures similar to those (step 7 and step 8) for compound 9, underappropriate conditions recognized by one of ordinary skill in the art.¹H NMR (400 MHz, DMSO-d₆) δ 7.38 (d, J=8.6 Hz, 2H), 7.00-6.94 (m, 3H),6.75 (br s, 1H), 6.69 (d, J=7.6 Hz, 1H), 6.51 (t, J=7.6 Hz, 1H), 6.28(d, J=7.6 Hz, 1H), 5.59-5.54 (m, 1H), 5.21 (br s, 1H), 4.11 (t, J=4.0Hz, 2H), 3.66 (t, J=4.0 Hz, 2H), 3.30 (s, 3H), 3.28-3.25 (m, 1H),3.02-2.92 (m, 1H), 2.24-2.16 (m, 1H) and 2.13-2.05 (m, 1H). MS (ESI) m/e[M+1]⁺ 407.9.

Compound 22:7-(2-Acrylamidophenyl)-2-(4-(2-methoxyethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from compound 21 and acryloyl chlorideaccording to procedure similar to that for compound 8. ¹H NMR (400 MHz,DMSO-d₆) δ 9.84 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.6, 2H),7.30 (t, J=7.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 6,93 (d, J=8.6 Hz, 2H),6.81 (s, 1H), 6.64 (d, J=8.0 Hz, 1H), 6.53 (dd, J=10.5, 17.0 Hz, 1H),6.27 (dd, J=1.7, 17.0Hz, 1H), 5.80-5.77 (m,2H), 4.11 (t, J=4.4Hz, 2H),3.66 (, J=4.4 Hz, 2H), 3.30 (s, 3H), 3.27-3.23 (m, 1H), 3.03-2.94 (m,1H), 2,36-2.25 (m, 1H), 2.01-1.95 (m, 1H). MS (ESI) m/e[M+1]⁺ 462.0.

Example 10 Synthesis of Compounds 23-24 Compound 23:7-(2-Aminophenyl)-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1:7-(2-Aminophenyl)-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (33 mg, 0.1 mmol) in THF (5 mL)was added PPh₃ (78.6 mg, 0.25 mmol) and tetrahydro-2H-pyran-4-ol (10 mg,0.1 mmol). Then, DIAD (51 mg, 0.25 mmol) was added dropwise to themixture at 0° C. and stirred at 0° C. for 10 min under N₂. The mixturewas allowed to warm to rt and stirred at RT for 16 hr. The mixture wasconcentrated in vacuum and partitioned between DCM (20 mL) and brine (20mL). Organic layer was separated from aqueous layers, dried over sodiumsulfate and purified by Pre-TLC (DCM/CH3OH=10/1) to afford 5 mg (12%) of7-(2-aminophenyl)-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as acolorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (d, J=8.4 Hz, 2H),7.66-7.58 (m, 2H), 7.58-7.52 (m, 1H), 7.03 (d, J=8.4 Hz, 2H), 6.97 (t,J=7.6 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 6.49 (t, J=7.6 Hz, 1H), 6.23 (d,J=8.0 Hz, 1H), 5.63 (s, 1H), 5.21 (s, 2H), 4.66-4.56 (m, 1H), 3.90-3.79(m, 2H), 3.54-3.43 (m, 2H), 3.25-3.18 (m, 1H), 2.97-2.86 (m, 1H),2.21-2.07 (m, 2H), 2.02-1.92 (m, 2H), 1.65-1.50 (m, 2H). MS (ESI) m/e[M+1]⁺ 415.9.

Step 2:7-(2-Aminophenyl)-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from7-(2-aminophenyl)-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile usingthe procedure similar to step 2 for compound 2. ¹H NMR (400 MHz,DMSO-d₆) δ 7.38 (d, J=8.8 Hz. 2H), 7.02 (d, J=8.8 Hz, 2H), 6.95 (t,J=7.6 Hz, 1H), 6.75 (s, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.49 (t, J=7.6 Hz,1H), 6.26 (d, J=7.8 Hz, 1H), 5.56 (s, 1H), 5.16 (s, 2H), 4.64-4.54 (m,1H), 3.91-3.79 (m, 2H), 3.53-3.42 (m, 2H), 3.29-3.19 (m, 1H), 3.01-2.92(m, 1H), 2.25-2.05 (m, 2H), 2.02-1.91 (m, 2H) and 1.64-1,52 (m, 2H). MS(ESI) m/e [M+1]⁺ 433.9.

Compound 24:7-(2-Acrylamidophenyl)-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from compound 23 and acryloyl chlorideusing the procedure similar to that for compound 8: ¹H NMR (400 MHz,DMSO-d₆) δ 9.83 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.6 Hz, 2H)7.30 (t, J=7.6 Hz, 1H), 7.21 (J=7.6 Hz, 1H), 7.02 (d, J=8.6 Hz, 2H),6.81 (s, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.53 (ddt J=17.0, 10.3 Hz, 1H),6.27 (dd, J=17.0, 1.6 Hz, 1H), 5.82-5.74 (m, 2H), 4.66-4.51 (m, 1H),3.90-3.78 (m, 2H), 3.54-3.40 (m, 2H), 3.31-3.18 (m, 1H), 3.03-2.93 (m,1H). 2.37-2.24 (m, 1H), 2.04-1.92 (m, 3H) and 1.64-1.51 (m, 2H). MS(ESI) m/e [M+1]⁺ 487.9.

Example 11 Synthesis of Compounds 25-27 Compound 25:7(1-(Tert-butoxycarbonyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from tert-butyl4-acetylpiperidine-1-carboxylate and5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile according to theprocedures for 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (step 4 to 5) and compound 2(step 1 and 2) under appropriate conditions recognized by one ofordinary skill in the art. ¹H NMR (CD₃OD-d₄) δ 7.40 (d, J=8.4 Hz, 2H),7.32-7.25 (m, 2H), 7.06 (t, J=7.6 Hz, 1H), 7.01-6.94 (m, 4H), 4.10-4.00(m, 2H), 3.98-3.91 (m, 1H), 3.35-3.30 (m, 2H), 2.70-2.58 (m, 2H),2.18-2.02 (m, 2H), 2.02-1.84 (m, 1H), 1.65-1.45 (m, 2H), 1.39-1.12 (m,2H), 1.35 (s, 9H). MS (EST) m/e [M+1]⁺ 518.0.

Compound 26:7-(Piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate

The desired product was prepared from compound 25 according to theprocedure similar to step 2 for compound 38. ¹H NMR (DMSO-d₆) δ 8.47 (brs, 1H), 8.16 (br s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.46-7.38 (m, 2H), 7.18(t, 7.6 Hz, 1H), 7.10-7.04 (m, 4H), 6.72 (br s, 1H), 4.08-4,01 (m, 1H),3.34-3.26 (m, 4H), 2.94-2.75 (m, 2H), 2.28-2.14 (m, 1H), 2:07-1.88 (m,2H), 1.87-1.80 (m, 1H), 1.75-1.66 (m, 1H), 1.60-1.43 (m, 2H). MS (ESI)m/e [M+1]⁺ 418.0.

Compound 27:7-(1-Acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from compound 26 and acryloyl chlorideaccording to the procedure similar to that for compound 8. ¹H NMR(DMSO-d₆) δ 7.50 (d, J=8.8 Hz, 2H), 7.46-7.38 (m, 2H), 7.17 (t, J=7.6Hz, 1H), 7.08 (d, J=7.6 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 6.83-6.76 (m,1H), 6.68 (br s, 1H), 6.07 (d, J=18.4 Hz, 1H), 5.64 (d, J=10.4 Hz, 1H),4.52-4.42 (m, 1H). 4.11-3.98 (m, 2H), 3.33-3:24 (m, 2H), 3.04-2.94 (m,1H). 2.67-2.55 (m, 1H), 2.33-2.25 (m, 1H), 2.01-1.93 (m,2H), 1.78-I;66(m, 1H), 1.61-1.50 (m, 1H), 1.30-1.18 (m, 2H), MS (ESI) m/e [M+1]⁺471.9.

Compound 27 was separated into two enantiomeric stereoisomers compound27a (peak 1, R or S, retention time at 6.49 min in chiral analysis), andcompound 27b (peak 2, S or R, retention time at 8.03 min in chiralanalysis) by chiral prep-HPLC. The chiral separation conditions areshown below.

Column CHIRALPAK IC Column size 2 cm × 25 cm Injection 2 mL Mobile phaseMeOH/ACN = 60/40 Flow rate 15 mL/min Wave length UV 254 nm Temperature35° C. Sample solution 0.5 mg/mL in mobile phase Prep-SFC equipmentDAICEL-YMC

The chiral analysis conditions are shown below.

Column CHIRALPAK IC Column size 0.46 cm I.D. × 15 cm L, 5 um Injection 2uL Mobile phase MeOH/ACN = 60/40 (v/v) Flow rate 1.0 mL/min Wave lengthUV 214, 254 nm

Example 12 Synthesis of Compounds 28-29 Compound 28:7-(Azetidin-3-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate

To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid(5.15 g, 25.6 mmol) in THF (100 mL) was added DCC (7.11 g, 34.5 mmol),Et₃N (5.18 g, 51.2 mmol) and N,O-dimethylhydroxylamine hydrochloride(3.44 g, 35.3 mmol), the reaction was stirred at RT for about 16 hr.Concentrated under reduced pressure to remove solvent, the residue wasportioned between EA (100 mL) and water (50 mL), the aqueous was furtherextracted with EA (50 mL×3). The combined organic phases were- washedwith brine (20 mL), concentrated under reduced pressure to removesolvent, then purified by column chromatography on silica gel (200-300mesh, CH₂Cl₂/MeOH=20/1) to give the crude product (−8.0 g) as acolorless oil. MS (ESI) m/e [M+23]⁺ 266.9. [M−55]⁺ 189.0.

Step 2: Tert-butyl 3-acetylazetidine-1-carboxylate

To a solution of tert-butyl3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (7.0 g, 28.7 mmol)in THF (150 mL) was added CH₃MgBr (43 mL, 43 mmol) at 0° C., then slowlywarmed to RT for about 2 hr. 10% aqueous of citric acid (30 mL) wasadded to the mixture, and extracted with EA (50 mL×3); the combinedorganic phases were washed with brine (20 mL), dried over Na₂SO₄,filtered, concentrated and purified by column chromatography on silicagel (200-300 mesh, PE/EA=2/1), to give the crude product (4.0 g, 70%) asa colorless oil. MS (ESI) m/e [M−55]⁺ 144.0.

Compound 28:7-(Azetidin-3-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from tert-butyl3-acetylazetidine-1-carboxylate and5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile according to theprocedures for 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazole[1,5-a]pyrimidine-3-carbonitrile (step 4 to 5), compound 2 (step 1 and2) and compound 38 (step 2), under appropriate conditions recognized byone of ordinary skill in the art. ¹H NMR (DMSO-d₆) δ 8.70 (br s, 1H),8.44 (br s, 1H), 7.50 (d, J=8.6 Hz. 2H), 7.45-7.40 (m, 2H), 7.18 (t,J=7.6 Hz, 1H), 7.08 (d, J=7.4 Hz, 2H), 7.06 (d, J=8.6 Hz, 2H), 6.72 (brs, 1H), 4.46-4.38 (m, 1H), 4.24-4.15 (m, 1H), 4.07-3.94 (m, 3H),3.29-3.24 (m, 2H), 3.19-3.10 (m, 1H), 2.13-2.04 (m, 1H), 1.78-1.69 (m,1H). MS (ESI) m/e [M+1]⁺ 390.0.

Compound 29:7-(1-Acryloylazetidin-3-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolor[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from compound 28 and acryloyl chlorideaccording to the procedure similar to that for compound 8. ¹H NMR(DMSO-d₆) δ 7.50 (d, J=8.4 Hz, 2H), 7.44-7.40 (m, 2H), 7.20-7.15 (m,1H), 7.10-7.04 (m, 4H), 6.69 (br s, 1H), 6.37-6.26 (m, 1H), 6.12-6.04(m, 1H), 5.68-560 (m, 1H), 4.43-4.25 (m, 2H). 4.18-4.08 (m, 1H),4.04-3.96 (m, 1H), 3.86-3.80 (m, 1H), 3.32-3.26 (m, 2H), 3.02-2.92 (m,1H), 2.14-2.06 (m, 1H), 1.79-1.70 (m, 1H). MS (ESI) m/e [M+1]⁺ 444:0.

Compound 29 was separated into two enantiomeric stereoisomers compound29a (peak 1, R or S, retention time at 10.54 min in chiral analysis),and compound 29b (peak 2, S or R, retention time at 13.98 min in chiralanalysis) by chiral prep-HPLC. The chiral separation conditions areshown below.

Column CHIRALCEL OJ-H Column size 2 cm × 25 cm Injection 3 ml Mobilephase CO₂/(MeOH70%ACN30%) = 75/25 Flow rate 45 ml/min Wave length UV 220nm Temperature 35 □ Sample solution 3 mg/ml in mobile phase Prep-SFCequipment DAICEL-SFC

The chiral analysis conditions are shown below.

Column CHIRALPAK AD Column size 0.46 cm I.D. × 15 cm L, 5 um Injection 3uL Mobile phase n-Hexane/EtOH (0.1% triethyl amine) = 70/30 (v/v) Flowrate 1.0 mL/min Wave length UV 214, 254 nm

Example 13 Synthesis of Compounds 30-31 Compound 30:Cis-7-Acryloyl-2-(4-phenoxyphenyl)-4,5,5a,6,7,8,9,9a-octahydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidine-3-carboxamide andCis-7-acryloyl-2-(4-phenoxyphenyl) -4,4a,5,6,7,8,8a,9-octahydropyrazolo[1,5-a]pyrido[4,3-d]pyrimidine-3-carboxamide

The desired product was prepared from tert-butyl4-oxopiperidine-1-carboxylate and5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile according to theprocedures for compound 27, under appropriate conditions recognized byone of ordinary skill in the an ¹H NMR (DMSO-d₆) δ 7.51 (d, J=8.4 Hz,2H), 7.46-7.38 (m, 2H), 7.17 (t, J=7.6 Hz, 1H), 7.11-7.01 (m, 4H),6.90-6.78 (m, 1H), 6.65 (s, 1H), 6.18-6.06 (m, 1H), 5.73-5.63 (m, 1H),4.45-4.33 (m, 1H), 3.84-3.34 (m, 5H), 3.22-3.16 (m, 1H), 2.40-2.32 (m,1H), 2.21-2.10 (m, 1H), 2.00-1.90 (m, 1H). MS (ESI) m/e [M+1]⁺ 443.9.

Compound 30 was separated into two enantiomeric stereoisomers compound30a (peak 1, R or S, retention time at 10.64 min in chiral analysis),and compound 30b (peak 2, S or R, retention time at 15.18 min in chiralanalysis) by chiral prep-HPLC. The chiral separation conditions areshown below.

Column CHIRALCEL ID Column size 3 cm × 25 cm Injection 7 mL Mobile phaseMeOH/EA = 30/70 Flow rate 25 ml/min Wave length UV 254 nm Temperature35° C. Sample solution 2 mg/ml in mobile phase Prep-SFC equipmentDAICEL-YMC

The chiral analysis conditions are shown below.

Column CHIRALPAK AD-H Column size 0.46 cm I.D. × 15 cm L, 5 um Injection3 uL Mobile phase n-Hexane/EtOH (0.1% triethyl amine) = 50/50 (v/v) Flowrate 1.0 mL/min Wave length UV 214, 254 nm

The compound 31 was obtained as one byproduct in the preparation ofcompound 30. ¹H NMR (DMSO-d₆ at 80° C.) δ 7.53 (d, J=8.4 Hz, 2H),7.46-7.38 (m, 2H), 7.17 (t, J=7.6 Hz, 1H), 7.11-7.02 (m, 4H), 6.82 (dd,J=16.8, 10.6 Hz, 1H), 6.42 (br s, 1H), 6.10 (dd, J=16.8, 2.3 Hz, 1H),6.01 (br s, 2H), 5.68 (dd, J=10.6, 2.3 Hz, 1H), 4.17 (dd, J=5.4, 12.2Hz, 1H), 3.67 (t, J=12.2 Hz, 1H), 3.28 (td, J=4.0, 10.4 Hz, 1H),2.24-2.17 (m, 1H), 1.93-1.81 (m, 1H), 1.47-1.33 (m, 1H). MS (ESI) m/e[M+1]⁺ 443.9.

Example 14 Synthesis of Compounds 32-33 Compound32:7-(Aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: (E)-2-(4-(Dimethylamino)-2-oxobut-3-enyl)isoindoline-1,3-dione

To a solution of 2-(2-oxopropyl)isoindoline-1,3-dione (1 g, 4.9 mmol) in20 mL of DMF-DMA was added some of 4A molecular sieve. The reactionmixture was stirred at 100° C. under N₂ for 15 hr. After cooling down toRT, the mixture was filtered and collected 600 mg (47.5%) of crude(E)-2-(4-(dimethylamino)-2-oxobut-3-enyl) isoindoline-1,3-dione as asolid. MS (ESI) m/e [M+1]⁺ 259.1.

Step 2:7-((1,3-Dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

A mixture of(E)-2-(4-(dimethylamino)-2-oxobut-3-enyl)isoindoline-1,3-dione (600 mg,2.33 mmol) and 5-amino-3-(4-phenoxy phenyl)-1H-pyrazole-4-carbonitrile(642 mg, 2.33 mmol) in 20 mL of HOAc was stirred and heated to 120° C.for 15 hr. The mixture was concentrated and suspended in 30 mL ofsolvent (PE/EA=4/1), The mixture was filtered and the solid was purifiedby pre-TLC (DCM/EA=50/1) to give 430 mg (40%) of7-((1,3-dioxoisoindoline-2-yl) methyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.74 (d, J=4.4 Hz, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.96-7.90 (m, 1H),7.88-7.85 (m, 2H), 7.50 (d, J=4.4 Hz, 1H), 7.46-7.37 (m, 2H), 7.21-7.09(m, 5H), 5.32 (s, 2H). MS (ESI) m/e [M+1]⁺ 472.1.

Step 3:7-(Aminomethyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of7-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (290 mg, 0.62 mmol) in 5 mL ofMeOH and 5 mL of dioxane was added 12 drops of hydrazine hydrate. Thereaction mixture was stirred and heated to 60° C. for 3 hr. The mixturewas concentrated and suspended in 20 mL of solvent (DCM/MeOH=10/1). Themixture was filtered and the filtrate was concentrated and purified bythe flash chromatography eluting with EA followed by DCM/MeOH (10/1) togive 150 mg (71%) of 7-(aminomethyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a solid. MS (ESI) m/e [M+1]⁺342.1.

Step 4:7-(Aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of7-(aminomethyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile(150 mg, 0.44 mmol) in 20 mL of EtOH was added NaBH₄ (200 mg). Thereaction mixture was stirred at rt for 15 hr. The mixture wasconcentrated to remove the solvent. The residue was partitioned betweenEA (20 mL) and water (20 mL). The organic layers were concentrated togive 150 mg (100%) of crude7-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a solid, which was used in the nextstep without further purification. MS (ESI) m/e [M+1]⁺ 346.0.

Step 5:7-(Aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of7-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (15 mg, 0.043 mmol) in 2 mL of EtOH wasadded 1 mL of DMSO, 0.5 mL of NaOH (5N) and 0.5 mL of H₂O₂ (30% aqueoussolution). After stirring at 60° C. for 2 hr, the mixture wasconcentrated to remove EtOH. The residue was partitioned between water(30 mL) and EA (20 mL). The organic phase was concentrated and purifiedby pre-HPLC eluting from 20% to 40% CH₃CN in 0.1% TFA in H₂O. Fractionscontaining the desired product were combined and lyophilized overnightto give the product as a TFA salt (10 mg, 64%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.07 (br s, 3H), 7.62 (d, J=8.8 Hz, 2H), 7.43-7.35 (m, 2H),7.25 (t, J=7.6 Hz, 1H), 7.15-7.12 (m, 4H), 6.77 (br s, 1H), 4.38-4.30(m, 1H), 3.40-3.20 (m, 4H), 2.16-2.06 (m, 1H), 2.00-1.80 (m, 1H). MS(ESI) m/e [M+1]⁺ 364.0.

Compound 33:7-(Acrylamidomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of7-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (125 mg, 0.344 mmol) in 5 mL of DCM wasadded Et₃N (four drops) and acryloyl chloride (46.5 mg, 0.52 mmol).After stirring at rt for 30 mins. The mixture was partitioned betweenwater (10 mL) and DCM (5 mL). The organic layer was concentrated andpurified by pre-TLC (DCM/MeOH=20/1) to give 40 mg (28%) of product. ¹HNMR (400 MHz, DMSO-d₆) δ 8.37 (t, J=6.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 2H),7.54-7.43 (m, 2H), 7.25 (t, J=7.6 Hz, 1H), 7.16-7.11 (m, 4H), 6.76 (s,1H), 6.33 (dd, J=10.1, 17.0 Hz, 1H), 6.18 (dd, J=1.9, 17.0 Hz, 1H), 5.69(dd, J=1.9, 10.1 Hz, 1H), 4.28-4.22 (m, 1H), 3.92-3.80 (m, 1H),3.50-3.30 (m, 3H), 2.14-1.94 (m, 2H). MS (ESI) m/e [M+1]⁺ 417.9.

Compound 33 was separated into two enantiomeric stereoisomers compound33a (peak 1, R or S, retention time at 6.04 min in chiral analysis), andcompound 33b (peak 2, S or R, retention time at 8.87 min in chiralanalysis) by chiral prep-HPLC. The chiral separation conditions areshown below.

Column CHIRALCEL AD-H Column size 3 cm × 25 cm Injection 5 mL Mobilephase CO₂/MeOH = 75/25 Flow rate 65 mL/min Wave length UV 220 nmTemperature 35 □ Sample solution 4.5 mg/mL in mobile phase Prep-SFCequipment DAICEL-SFC

The chiral analysis conditions are shown below.

Column CHIRALPAK AD-H Column size 0.46 cm I.D. × 15 cm L, 5 um Injection1 uL Mobile phase n-Hexane/EtOH (0.1% triethyl amine) = 70/30 (v/v) Flowrate 1.0 mL/min Wave length UV 214, 254 nm

Example 15 Synthesis of Compounds 34-35 Compound 34:7-((Methylamino)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1:N-((3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)-2,2,2-trifluoroacetamide

To a solution of7-(aminomethyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile(50 mg, 0.147 mmol) in 5 mL of DCM was added three drops of DIEA and twodrops of trifluoroacetic anhydride. After stirring at rt for 2 hr, 10 mLwater was added to the mixture and extracted with DCM (5 mL×2). The DCMlayers were concentrated to give a yellow solid (50 mg, 78%), which wasused in the next step without further purification.

Step 2:N-((3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)-2,2,2-trifluoro-N-methylacetamide

To a solution ofN-((3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)-2,2,2-trifluoroacetamide (40 mg, 0.091 mmol) in 5 mL of acetonewas added K₂CO₃ (50 mg) and CH₃I (0.5 mL). After stirring at rt for 4hr, the mixture was concentrated. The residue was partitioned between 10mL of water and 10 mL of DCM. The organic layer was concentrated andpurified by Pre-TLC (DCM/MeOH=20/1) to give a yellow solid (30 mg, 73%).MS (ESI) m/e [M+1]⁺ 451.9.

Step 3:7-((Methylamino)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution ofN-((3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl-2,2,2-trifluoro-N-methylacetamide (40 mg, 0.089 mmol) in 15 mL ofEtOH was added NaBH₄ (50 mg). After stirring at rt for 30 mins, themixture was concentrated. The residue was partitioned between 20 mL ofwater and 20 mL of EA. The EA layer was concentrated and purified byPre-TLC (DCM/MeOH=5/1) to give a white solid (20 mg, 63%). MS (ESI) m/e[M+1]⁺ 359.9.

Step 4:7-((Methylamino)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of7-((methylamino)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (20 mg, 0.0557 mmol) in 2 mL ofEtOH was added 1 mL of DMSO, 0.5 mL of NaOH (5N) and 0.5 mL of H₂O₂ (30%solution). The reaction mixture was stirred at 60° C. for 1 hr. Then themixture was concentrated to remove EtOH. The residue was partitionedbetween water (20 mL) and EA (20 mL). The EA layer was concentrated togive the product as a white solid (10 mg, yield: 48%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.51 (d, J=8 Hz, 2H), 7.47-7.40 (m, 2H), 7.19 (t, J=7.6 Hz,1H), 7.11-7.04 (m, 4H), 6.61 (s, 1H), 4.26-4.16 (m, 1H), 3.34-3.27 (m,2H), 2.97-2.95 (m, 1H). 2.83-2.77 (m, 1H), 2,33 (s, 3H). 2.08-2.02 (m,2H). MS (ESI) m/e [M+1]⁺ 378.0.

Compound 35:7-((N-Methyl(acrylamido)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrzolo[1,5-a]pyrimidine-3-carboxamide

To a solution of7-((methylamino)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (92 mg, 0.244 mmol) in 5 mL ofDCM was added Et₃N (three drops) and acryloyl chloride (33 mg, 0.366mmol). The reaction mixture was stirred at rt for 30 min. Then themixture was partitioned between water (30 mL) and DCM (20 mL). Theorganic layer was concentrated and purified by pre-TLC (DCM/MeOH=15/1)to give the product as a white solid (25 mg, yield: 24%). ¹H NMR (400MHz, DMSO-d₆ and D₂O at 80°C.) δ 7.51 (d, J=8.4 Hz, 2H), 7.44-7.39 (m,2H), 7.20-7.14 (m, 1H), 7.10-7.04 (m, 4H), 6.75-6.57 (m, 2H), 6.10-5.85(m, 1H), 5.67-5.50 (m, 1H), 4.45-4.38 (m, 1H), 4.00-3.70 (m, 2H),3.40-3.30 (m, 2H), 3.00 (s, 3H), 2.14-1.90 (m, 2H). MS (ESI) m/e [M+1]⁺432.0.

Example 16 Synthesis of Compounds 36-37 Compound 36:7-(Aminomethyl)-2-(1-benzyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate

Step 1: Ethyl 1-benzyl-1H-pyrazole-4-carboxylate

To a mixture of ethyl 1H-pyrazole-4-carboxylate (35.0 g, 250 mmol) andK₂CO₃ (69.0 g, 500 mmol) in CH₃CN (250 mL) was added BnBr (42.7 g, 250mmol). The mixture was stirred at RT for 18 h and concentrated. Theresidue was suspended in EA (500 mL), washed with water (200 mL×2),dried over Na₂SO₄ and concentrated to give the desired compound as awhite solid (53.0 g, 91.2%). ¹H NMR (DMSO-d₆) δ 8.46 (s, 1H), 7.88 (s,1H), 7.41-7.19 (m, 5H), 5.37 (s, 2H), 4.21 (q, 2H, J=5.4 Hz), 1.25 (t,3H, J=5.4 Hz). MS (ESI) m/e [M+1]⁺ 231.0.

Step 2: 1-Benzyl-1H-pyrazole-4-carboxylic acid

A mixture of ethyl 1-benzyl-1H-pyrazole-4-carboxylate (53.0 g, 0.23 mol)and LiOH (19.4 g, 0.46 mol) in THF (100 mL) and H₂O (100 mL) was stirredat refluxed for 6 h. Then, THF was removed, the residue was acidify by 6N HCl, precipitation was formed, filtered and dried to give the desiredcompound as a white solid (44.0 g, 92.8%). ¹H NMR (DMSO-d₆) δ 12.36 (s,1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.38-7.27 (m, 5H), 5.37 (s, 2H). MS(ESI) m/e [M+1]⁺ 202.9.

Step 3: 2-((1-Benzyl-1H-pyrazol-4-yl)(hydroxy)methylene)malononitrile

A solution of 1-benzyl-1H-pyrazole-4-carboxylic acid (25.0 g, 123.8mmol) in SOCl₂ (250 mL) was heated to reflux for 3 hr. The mixture wasconcentrated in vacuum to give the intermediate, which was used in thenext step without further purification. To a solution ofpropanedinitrile (8.2 g, 12.8 mmol), DIEA (32.0 g, 247.6 mmol) in THF(250 mL) was added dropwise a solution of intermediate in toluene (250mL) at 0-5° C. over 1 hr.The resultant mixture was allowed to warm to RTand stirred for 16 hr. The reaction was quenched with water (500 mL) andextracted with EA (500 mL×3). The organic layers were washed with 3 NHCl (500 mL), brine (500 mL×3), dried over Na₂SO₄ and concentrated togive the crude product (26.5 g, 85.0%) as a yellow solid. MS (ESI) m/e[M+1]⁺ 250.9.

Step 4: 2-((1-Benzyl-pyrazol-4-yl)(methoxy)methylene)malononitrile

A solution of2-((1-benzyl-1H-pyrazol-4-yl)(hydroxy)methylene)malononitrile (26.5 g,106 mmol) in CH(OMe)₃ (250 mL) was heated to 75° C. for 16 hr. Then thesolution was concentrated. The residue was washed with MeOH (50 mL) togive 14.5 g (51.8%) of 2-((1-benzyl-1H-pyrazol-4-yl)(methoxy)methylene)malononitrile as an off-white solid. ¹H NMR (DMSO-d₆)δ 8.71 (s, 1H), 8.08 (s, 1H), 7.42-7.24 (m, 5H), 5.46 (s, 2H), 4.12,(s,3H). MS (ESI) m/e [M+1]⁺ 264.9.

Step 5: 5-Amino-2′-benzyl-3,4′-bi(1H-pyrazole)-4-carbonitrile

A mixture of2-((1-benzyl-1H-pyrazol-4-yl)(methoxy)methylene)malononitrile (14.5 g,54.9 mmol) and hydrazine hydrate (10 mL) in EtOH (500 mL) was stirred atRT for 4 hr. Then the mixture was concentrated to give the crudeproduct, washed with MeOH to afford 10 g (69.0%) of5-amino-2′-benzyl-3,4′-bi(1H-pyrazole)-4-carbonitrile as an off-whitesolid. ¹H NMR (DMSO-d₆) δ 11.76 (br s, 1H), 8.18 (s, 1H), 7.82 (s, 1H),7.34-7.26 (m, 5H), 6.11 (br s, 2H), 5.40 (s, 2H). MS (ESI) m/e [M+1]⁺264.9.

Compound 36:7-(Aminomethyl)-2-(1-benzyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate

The desired product was prepared from5-amino-2′-benzyl-3,4′-bi(1H-pyrazole)-4-carbonitrile and(E)-2-(4-(dimethylamino)-2-oxobut-3-enyl)isoindoline-1,3-dione accordingto the procedures (step 2 to 5) for compound 32, under appropriateconditions recognized by one of ordinary skill in the art. ¹H NMR (400MHz, DMSO-d₆) δ 8.14 (s, 1H), 7.97 (br s, 3H), 7.74 (s, 1H), 739-7.24(m, 5H), 5.37 (s, 2H), 4.40-4.25 (m, 1H), 3.37-3.16 (m, 4H), 2.16-2.08(m, 1H), 1.99-1.89 (m, 1H). MS (ESI) m/e [M+1]⁺ 352.0.

Compound 37:7-(Acrylamidomethyl)-2-(1-benzyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from compound 36 and acryloyl chlorideusing the procedure similar to that for compound 8. ¹H NMR (400 MHz,DMSO-d₆) δ 8.27 (t, J=6.1 Hz, 1H), 8.11 (s, 1H), 7.67 (s, 1H), 7.41-7.21 (m, 5H), 6.58 (s, 1H), 6,25 (br s, 2H), 6.25 (dd, J=17.1, 10.1 Hz,1H), 6.10 (dd, J=17.1, 2.1 Hz, 1H), 5.62(dd, J=10.1, 2.1 Hz, 1H), 5.36(s, 2H), 4.16-4.10 (m, 1H), 3.83-3.72 (m, 1H), 3.42-3.30 (m, 1H),3.30-3.22 (m, 2H), 2.00-1.96 (m, 1H), 1.95-1.86 (m, 1H). MS (ESI) m/e[M+1]⁺ 405.9.

Example 17 Synthesis or Compounds 38-40 Compound 381′-Benzyl-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4-piperidine]-7-carboxamide

Step 1: di-tert-Butyl1-(1-benzyl-4-(ethoxycarbonyl)piperidin-4-yl)hydrazine-1,2-dicarboxylate

To a solution of diisopropylamine (153 mg, 1.5 mmol) in THF (20 mL) wasadded n-BuLi (2.5 M, 0.6 mL) al −75° C. under N₂. After 5 min, ethyl1-benzylpiperidine-4-carboxylate (247 mg, 1.0 mmol) was added and theresulting mixture then stirred at −70° C. for 10 min, before addingdi-tert-butyl azodicarboxylate (345 mg, 1.5 mmol). The reaction wasstirred for 30 min, then quenched with aqueous NH₄Cl (10 mL) andextracted with EA (10 mL×3). The combined organic layers were dried overNa₂SO₄ and concentrated to give the crude product (350 mg, 72%) as anoff-white solid. MS (ESI, m/e) [M+1]⁺ 478.3.

Step 2: Ethyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylatehydrochloride

A mixture of di-tert-butyl1-(1-benzyl-4-(ethoxycarbonyl)piperidin-4-yl)hydrazine-1,2-dicarboxylate(1.0 g, 2.09 mmol) and con. HCl (1.0 mL) in MeOH (10 mL) was heated toreflux for 2 hr. The mixture was then concentrated to give the crudeproduct (650 mg, 88.9%) as a yellow solid. MS (ESI, m/e) [M+1]⁺ 278.0.

Step 3: Ethyl4-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-1-benzylpiperidine-4-carboxylate

A mixture of ethyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylatehydrochloride (580 mg, 1.57 mmol),2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (433 mg, 1.57 mmol)and TEA (475 mg, 4.71 mmol) in CHCl₃ (20 mL) was heated to reflux for 16hr under N₂. The mixture was concentrated and purified by chromatographycolumn on silica gel using 50% of EA in PE as eluant to give the product(280 mg 34.2%) as a yellow solid. MS (ESI, m/e) [M+1]⁺ 521.9.

Step 4:5-Amino-1-(1-benzyl-4-(hydroxymethyl)piperidin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile

To a solution of ethyl4-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-1-benzylpiperidine-4-carboxylate(52 mg, 0.1 mmol) in MeOH (5 mL) was added NaBH₄ (8 mg, 0.2 mmol). After10 min, the reaction was quenched with water (5 mL) and extracted withEA (10 mL×3). The organic combined layers was dried over Na₂SO₄ andconcentrated to give the crude product (34 mg, 70.9%) as an off-whitesolid. MS (ESI, m/e) [M+1]⁺ 480.0.

Step 5:(4-(5-Amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-1-benzylpiperidin-4-yl) methyl methanesulfonate

To a solution of5-amino-1-(1-benzyl-4-(hydroxymethyl)piperidin-4′yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile(50 mg, 0.1 mmol) and TEA (20 mg, 0.20 mmol) in DCM (5 mL) was addedMsCl (14 mg, 0.12 mmol) at 0°C. After 5 min, the reaction was quenchedwith water (5 mL) and extracted with DCM (5 mL×3). The combined organiclayers were dried over Na₂SO₄ and concentrated and purified by Prep-TLC(10% of MeOH in DCM) to give the product (35 mg, 62.8%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (d, J=8.8 Hz, 2H), 7.45-7.36 (m,2H), 7.37-7.22 (m, 5H), 7.17 (t, J=7.6 Hz, 1H), 7.11 (d, J=8.8 Hz, 2H),7.06 (d, J=8.0 Hz, 2H), 6.49 (br s, 2H), 4.48 (s, 2H), 3.40 (s, 2H),3.10 (s, 3H), 2.88-2.55 (m, 4H), 2.19-2.16 (m, 2H), 1.92-1.86 (m, 2H).MS (ESI, m/e) [M+1]⁺ 557.9.

Step 6:1′-Benzyl-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carbonitrile

A mixture of(4-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-1-benzylpiperidin-4-yl)methyl methanesulfonate (35 mg, 0.06 mmol) and Cs2CO3 (31 mg, 0.09 mmol)in DMF (2 mL) was heated to 50° C. for 16 hr. The reaction was quenchedwith water (5 mL) and extracted with EA (5 mL×3). The combined organiclayers were dried over Na₂SO₄, concentrated and purified by Prep-TLC(10% of MeOH in DCM) to give the product (12 mg, 43.2%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.79 (d, J=8.4 Hz, 2H), 7.43-7.40 (m,3H), 7.38-7.29 (m, 4H), 7.26 (br s, 1H), 7.19 (t, J=7.6 Hz, 1H),7.12-7.05 (m, 4H), 3.85 (s, 2H), 3.53 (s, 2H), 2.89-2.80 (m, 2H),2.22-2.12 (m, 2H), 2.10-1.96 (m, 2H), 1.85-1.75 (m, 2H). MS (ESI, m/e)[M+1]⁺ 462.0.

Step 7:1′-Benzyl-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carboxamide

The desired product was prepared from1′-benzyl-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carbonitrile according to theprocedure similar to step 2 for compound 2. ¹H NMR (400 MHz, DMSO-d₆) δ7.63 (d, J=8.4 Hz, 2H), 7.45-7.39 (m, 3H), 7.37-7.31 (m, 4H), 7.16 (t,J=7.6 Hz, 1H), 7.12-6.94 (m, 4H), 6.43 (s, 1H), 3.78 (s, 2H), 3.55 (brs, 2H), 2.89-2.82 (m, 2H), 2.15-2.11 (m, 2H), 1.84-1.72 (m, 2H). MS(ESI, m/e) [M+1]⁺ 479.9.

Compound 39:6-(4-Phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carboxamide

A mixture of1′-benzyl-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carboxamide (50 mg, 0.10 mmol), 10% w/w Pd(OH)₂/e (5 mg) in MeOH (10mL) and HOAc (1 drop) was stirred for 16 hr under H₂. The mixture wasfiltrated and the filtrate was concentrated to give the crude product(20 mg 51.4%) as a yellow solid. MS (ESI, m/e) [M+1]⁺ 390.0.

Compound 40:1′-Acryloyl-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carboxamide

Compound 40 was prepared from compound 39 and acryloyl chlorideaccording to the procedure similar to that for compound 8. ¹H NMR (400MHz, DMSO-d₆) δ 7.64 (d, J=8.8 Hz, 2H), 7.44-7.37 (m, 2H), 7.16 (t,J=7.6 Hz, 1H), 7.05 (d, J=7.6 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.86 (dd,J=10.5, 16.7 Hz, 1H), 6.51 (br s, 1H), 6.12 (dd, J=2.3, 16.7 Hz, 1H),5.69 (dd, J=2.3, 10.5 Hz, 1H), 4.13-3.95 (m, 2H), 3.83 (s, 2H),3.60-3.38 (m, 2H), 1.99-1.76 (m, 4H). MS (ESI, m/e) [M+1]⁺ 443.9.Example 18 Synthesis of Compounds 41-43 Compound 41:1-Benzyl-2′-(4-phenoxyphenyl)-5′,6′-dihydro-4′H-spiro[piperidine-4,7-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide

Step 1: Ethyl 2-(1-benzylpiperidin-4-ylidene)acetate

To a suspension of NaH (318 mg, 7.94 mmol) in THF (20 mL) was added asolution of ethyl 2-(diethoxyphosphoryl)acetate (1.78 g, 7.94 mmol) inTHF (5 mL) dropwise over 30 min at 0°C. After stirring for 10 min, asolution of 1-benzylpiperidin-4-one (1.0 g, 5.29 mmol) in THF (5 mL) wasadded dropwise at 0° C. over 20 min. The mixture was allowed to stir for60 min. Then, the reaction was quenched with water (10 mL). The mixturewas extracted with EA (10 mL×3). The combined organic layers were driedover Na₂SO₄, concentrated and purified by chromatography column onsilica gel using 25% of EA in PE as eluant to give the product (1.2 g,87.3%) as a yellow oil. MS (ESI, m/e) [M+1]⁺ 260.0.

Step 2:1-Benzyl-5′-oxo-2′-(4-phenoxyphenyl)-5′,6′-dihydro-4′H-spiro[piperidine-4,7′-pyrazolo[1,5-a]pyrimidine]-3′-carbonitrile

A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (1.0g, 3.6 mmol), ethyl 2-(1-benzylpiperidin-4-ylidene)acetate (1.1 g, 4.3mmol) and K₂CO₃ (745 mg, 5.4 mmol) in DMF(20 mL) was healed to 80° C.for 16 hr under N₂. The reaction was quenched with water (20 mL) andextracted with EA (20 mL×3). The combined organic layers were dried overNa₂SO₄, concentrated and purified by chromatography column on silica gelusing 30% of EA in PE as eluant to give the product (950 mg, 54.9%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1H), 7.84 (d, J=8.8Hz, 2H), 7.48-7.40 (m, 2H), 7.36-7.29 (m, 4H), 7.27-7.23 (m, 1H), 7.20(t, J=7.6 Hz, 1H), 7.15-7.07 (m, 4H), 3.55 (s, 2H), 3.01 (s, 2H),2.81-2.73 (m, 2H), 2.39-2.27 (m, 2H), 2.26-2.16 (m, 2H), 1.83-1.74 (m,2H). MS (ESI, m/e) [M+1]⁺ 489.9.

Step 3:1-Benzyl-5′-oxo-2′-(4-phenoxyphenyl)-5′,6′-dihydro-4′H-spiro[piperidine-4,7′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide

A solution of1-benzyl-5′-oxo-2′-(4-phenoxyphenyl)-5′,6′-dihydro-4′H-spiro[piperidine-4,7′-pyrazolo [1,5-a]pyrimidine]-3′-carbonitrile (500 mg,1.02 mmol) in H₃PO₄ (5 mL) was healed to 130° C. for 1 hr. The mixturewas poured to water (20 mL) and extracted with EA (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, concentrated andpurified by chromatography column on silica gel using 5% of MeOH in DCMas eluant to afford the product (180 mg, 34.8%) as a yellow solid. MS(ESI, m/e) [M+1]⁺ 507.9.

Step 4:1-Benzyl-5′-(4-phenoxyphenyl)-5′,6′-dihydro-4′H-spiro[piperidine-4,7′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide

A solution of1-benzyl-2′-oxo-2′-(4-phenoxyphenyl)-5′,6′-dihydro-4′H-spiro[piperidine-4,7′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide (180 mg, 0.36mmol) in BH3/THF (1N, 20 mL) was heated to reflux for 3 hr. The reactionwas quenched with MeOH (20 mL) and con. HCl (2 mL). The mixture wasstirred al 60° C. for 1 hr, then was basified with NaHCO₃ and extractedwith EA (20 mL×3). The combined organic layers were dried over Na₂SO₄,concentrated and purified by chromatography column on silica gel elutingwith 5% of MeOH in DCM to give the product (120 mg, 67.6%) as a yellowsolid. ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.39-7.22 (m, 9H), 7.09-7.04 (m,1H), 6.99-6.94 (m, 4H), 3.86 (s, 2H), 3.35 (t, J=5.6 Hz, 2H), 3.19-3.11(m, 2H), 2.80-2.66 (m, 2H), 2.50-2.40 (m, 2H), 2.10 (t, J=5.6 Hz, 2H),1.87-1.78 (m, 2H). MS (ESI, m/e) [M+1]⁺ 493.9.

Compound 42:2′-(4-Phenoxyphenyl)-5′,6′-dihydro-4′H-spiro[piperidine-4,7′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide trifluoroacetate

Compound 42 was prepared from1-benzyl-2′-(4-phenoxyphenyl)-5′,6′-dihydro-4′H-spiro [piperidine-4,7′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide according to the proceduresimilar to that for compound 39. ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (br s,2H), 7.51 (d, J=8.6 Hz, 2H), 7.46-7.37 (m, 2H), 7.18 (t, J=7.6 Hz, 1H),7.11-7.04 (m, 4H), 6.79 (s, 1H), 3.40-3.33 (m, 4H), 3.17-3.06 (m, 2H),2.46-2,35 (m, 2H), 2.17-2.10 (m, 2H), 1.96-1.87 (m, 2H). MS (ESI, m/e)[M+1]⁺ 403.9. Compound 43:1-Acryloyl-2′-(4-phenoxyphenyl)-5′,6′-dihydro-41H-spiro[piperidine-4,7′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide

Compound 43 was prepared from compound 42 and acryloyl chlorideaccording to the procedure similar to that for compound 8. ¹H NMR (400MHz, DMSO-d₆) δ 7.50 (d, J=8.8 Hz, 2H), 7.45-7.37 (m, 2H), 7.17 (t,J=7.2 Hz, 1H), 7.12-7.01 (m, 4H), 6.85 (dd, J=10.4, 16.7 Hz, 1H), 6.73(s, 1H), 6.11 (dd, J=2.4, 16.7 Hz, 1H), 5.68 (dd, J=2.4, 10.4 Hz, 1H),4.23 (d, J=13.2 Hz, 1H), 4.03 (d, J=13.2 Hz, 1H), 3.43 (t, J=12.0, 1H),3.37-3.33 (m, 2H), 3.16 (t, J=12.0 Hz, 1H), 2.24-2.08 (m, 4H), 1.82-1.73(m, 2H). MS (ESI, m/e) [M+1]⁺ 457:9. Example 19 Synthesis of Compounds44-46 Compound 44:1-Benzyl-6,-(4-phenoxyphenyl)-1′2′-dihydrospiro[azetidine-3,3′-imidazo[1,2-b]pyrazole]-7′-carboxamide

Step 1: Methyl 1-benzylazetidine-3-carboxylate

To a solution of methyl azetidine-3-carboxylate (5.0 g, 33.1 mmol) andDIEA (10.7 g, 82.8 mmol) in DMF (50 mL) was added dropwise bromomethylbenzene (5.7 g, 33.1 mmol) at 0 UC over 10 min. After stirring for 2 hrat rt, the mixture was poured to water (50 mL) and extracted with EA (50mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated and purified by chromatography column on silica (EA/PE=¼)to give the product (3.5 g, 51.6%) as a light yellow oil, ¹H NMR(DMSO-d₆) δ 7.34-7.20 (m, 5H), 3.62 (s, 3H), 3.53 (s, 2H), 3.41-3.35 (m,1H), 3.29-3:31 (m, 2H), 3.19-3.22 (m, 2H). MS (ESI, m/e) [M+1]⁺ 206.0.

Step 2: Di-tert-butyl1-(1-benzyl-3-(methoxycarbonyl)azetidin-3-yl)hydrazine-1,2-dicarboxylate

The desired product was prepared from methyl1-benzylazetidine-3-carboxylate and ditert-butyl azodicaiboxylate usingthe procedure similar to step 1 for compound 38. MS (ESI, m/e) [M+1]⁺435.9.

Step 3 to 5:5-Amino-1-(1-benzyl-3-(hydroxymethyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile

The desired product was prepared from di-tert-butyl1-(1-benzyl-3-(methoxycarbonyl)azetidin-3-yl)hydrazine-1,2-dicarboxylate using the procedures similarto those (step 2 to 4) for compound 38. ¹H NMR (DMSO-d₆) δ 7.78 (d,J=8.8 Hz, 2H), 7.46-7.38 (m, 2H), 7.36-7.21 (m, 5H), 7.18 (t, J=7.6 Hz,1H), 7.11-7.04 (m, 4H), 6.17 (s, 2H), 5.50 (t, J=5.2 Hz, 1H), 3.89 (d,J=5.2 Hz, 2H), 3.61-3.63 (m,4H). 3.38 (d, J=6.4 Hz, 2H). MS (ESI, m/e)[M+1]⁺ 451.9.

Step 6:(3-(5-Amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-1-benzylazetidin-3-yl) methyl methanesulfonate

The desired product was prepared from5-amino-1-(1-benzyl-3-(hydroxymethyl)azetidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile using the procedure similar to step 5for compound 38. ¹H NMR (DMSO-d₆) δ 7.82-7.74 (m, 2H), 7.46-7.38 (m,2H), 7.36-7.23 (m, 5H), 7.21-7.15 (m, 1H), 7.13-7.04 (m, 4H), 6.52 (s,2H), 4.69 (s, 2H), 3.70 (d, J=8.4 Hz, 2H), 3.66 (s, 2H), 3.49 (d, J=8.4Hz, 2H), 3.13 (s, 3H). MS (ESI, m/e) [M+1]⁺ 529.9.

Step 7. 8:1-Benzyl-6,-(4-phenoxyphenyl)-1′,2′-dihydrospiro[azetidine-3,3,-imidazo[1,2-b]pyrazole]-7′-carboxamide

The desired product was prepared from(3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-1-benzylazetidin-3-yl)methyl methanesulfonate using the procedures similar tothose (step 6 and 7) for compound 38. ¹H NMR (DMSO-d₆) δ 7.66 (d, J=8.8Hz, 2H), 7.46-7.38 (m, 2H), 7.35-7.28 (m, 4H), 7.28-7.21 (m, 1H), 7.16(t, J=7.6 Hz, 1H), 7.06 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.52(s, 1H), 4.19 (s, 2H), 3.67 (s, 2H), 3.54 (s, 4H). MS (ESI, m/e) [M+1]⁺451.9.

Compound 45:6′-(4-Phenoxyphenyl)-1′,2′-dihydrospiro[azetidine-3,3′,-imidazo[1,2-b]pyrazole]-7′-carboxamide

The desired product was prepared from compound 44 using the proceduresimilar to that for compound 39. ¹H NMR (DMSO-d₆) δ 7.67 (d, J=8.4 Hz,2H), 7.46-7.36 (m, 2H), 7.16 (t, J=7.6 Hz, 1H). 7.06 (d, J=7.6 Hz, 2H),7.00 (d, J=8.4 Hz, 2H), 6.62 (s, 1H), 4.19-4.20 (m, 4H), 3.78 (d, J=9.6Hz, 2H). MS (ESI, m/e) [M+1]⁺ 361.9.

Compound 46:1-Acryloyl-6′-(4-phenoxyphenyl)-1′,2′-dihydrospiro[azetidine-3,3′-imidazo[1,2-b]pyrazole]-7′-carboxamide

The desired product was prepared from compound 45 and acryloyl chlorideusing the procedure similar to that for compound 8. ¹H NMR (DMSO-d₆) δ7.66 (d, J=8.8 Hz, 2H), 7.45-7.37 (m, 2H), 7.16 (t, J=7.6 Hz, 1H), 7.06(d, J=7.6 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 6.62 (s, 1H), 6.36 (dd,J=17.0. 10.3 Hz, 1H), 6.15 (dd, J=17.0, 2.1 Hz, 1H), 5.72 (dd, J=10.3,2.1 Hz, 1H), 4.62 (d, J=9.6 Hz, 1H), 4.56 (d, J=9.6 Hz, 1H), 4.32 (d,J=11.2 Hz, 1H), 4.27 (d, J=11.2 Hz, 1H), 4.22 (s, 2H). MS (ESI, m/e)[M+1]⁺ 415.9.

Example 20 Synthesis or Compounds 47-50 Compound 47:2-(3-Aminophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide

Step 1: 5-Amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

A solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile(1.0 g, 3.6 mmol) in H₃PO₄ (20 mL) was heated to 120° C. for 4 hr. Themixture was then poured into water (100 mL), extracted with EA (100mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated to give the product (850 mg, 77.5%) as yellow solid, MS(ESI, m/e) [M+1]⁺ 295.1.

Step 2:2-(3-Nitrophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide

A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (29.4mg, 0.1 mmol) and 2-bromo-1-(3-nitrophenyl)ethanone (24.4 mg, 0.1 mmol)in EtOH (2 mL) was stirred at 80° C. for 16 hr. The mixture was filteredto afford 5 mg of crude 2-(3-nitrophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide as a yellow solid. MS (ESI) m/e [M+1]⁺440.0.

Step 3:2-(3-Aminophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide

To a solution of 2-(3-nitrophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide (600 mg, 1.37 mmol) in 10 mL of MeOH and 10 mL ofDCM was added 10% w/w Pd/C (100 mg). After stirring at RT under 1 h for4 hr, the mixture was filtered. The filtrate was concentrated andpurified by Pre-HPLC eluting from 30% to 90% CH₃CN in 0.1% TFA in H₂O.Fractions containing the desired product were combined and lyophilizedovernight to afford 73 mg (13%) of2-(3-aminophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamideas a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (d, J=10.4 Hz, 1H),8.14 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.47-7.40 (m, 2H),7.38-7.26 (m, 3H), 7.18 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.0 Hz, 2H), 7.03(d, J=8.4 Hz, 2H) and 6.98-6.86 (m, 2H). MS (ESI) m/e [M+1]⁺ 409.9.

Compound 48:2-(3-Acrylamidophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide

The desired product was prepared from2-(3-aminophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide and acryloyl chloride using the proceduresimilar to that for compound 8. ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.06 (s,1H), 7.83 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.52-7.38 (m, 5H), 7.15 (t,J=7.6 Hz, 1H), 7.09-7.05 (m, 4H), 6.49-6.37 (m, 2H) and 5.80 (dd, J=4.0,8.8 Hz, 1H). MS (ESI) m/e [M+1]⁺ 463.9.

Compound 49:3-(3-Aminophenyl)-6-(4-phenoxyphenyl)-1H-pyrazolo[1,5-a]imidazole-7-carboxamide

The desired compound was separated as another isomer in the step 2 ofcompound 48. ¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (d, J=2.4 Hz, 1H), 8.03(s, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.81-7.68 (m, 3H), 7.46-7.37 (m, 4H),7.19 (t, J=7.6 Hz, 1H), 7.13-7.08 (m, 5H) and 6.98 (d, J=7.6 Hz, 1H). MS(ESI) m/e [M+1]⁺ 410.1.

Compound 50:3-(3-Acrylamidophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide

The desired product was prepared from compound 49 and acryloyl chlorideusing the procedure similar to compound 8. ¹H NMR (400 MHz, DMSO-d₆) δ12.18 (d, J=2.4 Hz, 1H), 10.31 (s, 1H), 8.38 (s, 1H), 7.85 (d, J=8.0 Hz,1H), 7.80-7.73 (m, 4H) 7.46-7.40 (m, 3H), 7.19 (t, J=8.0 Hz, 1H),7.13-7.07 (m, 4H), 6.50 (dd, J=10.2, 17.0 Hz, 1H), 6.27 (d, J=17.0 Hz,1H), 5.76 (d, J=10.2 Hz, 1H). MS (ESI) m/e [M+1]⁺ 463.9.

Example 21 Synthesis of Compounds 51 to 60 Compound 51:2-(4-Phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamidetrifluoroacetate

Step 1: tert-Butyl 3-bromo-4-oxopiperidine-1-carboxylate

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25 mmol)in 30 mL of DMF at RT was added TEA (7.7 mL, 55 mmol) followed by TMSCl(3.5 mL, 27.6 mmol), then the mixture was stirred at 75° C. overnight.The reaction was cooled to RT, cold sat. aq. NaHCO₃ (200 mL) was addedfollowed by cold hexane (200 mL). The organic layer was washed withbrine, dried over Na₂SO₄, concentrated to get the crude product directlyused in the next step. The residue was dissolved in 15 mL of THF andstirred at 0° C. for 15 min. A solution of NBS (4.47 g, 25 mmol) in 80mL of THF was added slowly. After addition, the reaction was stirred atRT overnight. Water (200 mL) was added to the reaction followed by 200mL of hexane. The organic layer was washed with brine, dried over Na₂SO₄and concentrated to get crude product which was chromatographed on 60 gof silica gel using PE/EA (20/1 to 8/1) as eluant to afford 5.56 g (78%)of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 4.85-4.70 (m, 1H), 4.20-4.00 (m, 1H), 3.90-3.55(m, 3H), 2.80-2.68 (m, 1H), 2.54-2.44 (m, 1H), 1.43 (s, 9H). MS (ESI)m/e [M-t-Bu]⁺ 221.9, 224.0.

Step 2: tert-Butyl3-cyano-2-(4-phenoxyphenyl)-5,6-dihydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-7(8H)-carboxylate

A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (1.5g, 5.4 mmol) and K₂CO₃ (2.24 g, 16.3 mmol) in 50 mL of DMF at 80° C. wasstirred under N₂ for 45 min before tert-butyl3-bromo-4-oxopiperidine-1-carboxylate (4.5 g, 16.3 mmol) was added inone portion. Then the mixture was stirred at 80° C. for 1 hr. Aftercooling down to RT, 150 mL of water and 150 mL of EA was added. Aqueousphase was further extracted with EA (100 mL ×3). The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated to gelcrude product which was chromatographed on 15 g of silica gel usingDCM/MeOH (400/1 to 200/1) as eluant to afford 850 mg (35%) of tert-butyl3-cyano-2-(4-phenoxyphenyl)-5,6-dihydro -4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-7(8H)-carboxylate as an off-whitesolid, MS (ESI) m/e [M+1]⁺ 455.9.

Step 3:2-(4-Phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamidetrifluoroacetate

A solution of tert-butyl3-cyano-2-(4-phenoxyphenyl)-5,6-dihydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-7(8H)-carboxylate (130 mg, 0.28 mmol)in H₃PO₄ (85 wt. % in H₂O, 20 mL) was stirred at 100° C. for 1.5 hr,until TLC and LCMS analysis showed that most of starting material wasconsumed. The mixture was cooled to room temperature and poured intowater (100 mL). The mixture was adjust to PH=9-10 with solid K₂CO₃. Thesuspension was extracted with EA (100 mL×4). The combined organic layerswere washed with brine (200 mL), dried over Na₂SO₄ and concentrated toget the crude product which was purified with pre-HPLC eluting from 10%to 90% CH3CN in 0.1% TFA in H₂O. Fractions containing the desiredproduct were combined and lyophilized overnight to give 15 mg (11%) of2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide trifluoroacetate as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, 1H), 9.32 (s, 2H),7.66 (d, J=8.6 Hz, 2H), 7.43 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H),7.18 (t, J=7.6 Hz. 1H), 7.10-7.06 (m, 4H), 4.44 (s, 2H), 3.49 (m, 2H),2.95-2.92 (m, 2H), MS, (ESI) m/e [M+1]⁺ 373.9.

Compound 52:7-Acryloyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide

The desired product was prepared from compound 51 and acryloyl chlorideusing the procedure similar to that for compound 8. ¹H NMR (400 MHz,DMSO-d₆ at 80°C.) δ 11.55. (s, 1H), 7.71 (d, J=8.6 Hz, 2H), 7.43 (d,J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.10-7.05(m, 4H), 6.88 (dd, J=10.6, 17.1 Hz, 1H), 6.24 (s, 2H), 6.15 (d, J=17.1Hz, 1H), 5.74 (d, J=10.6 Hz, 1H), 4.78 (s, 2H), 3.94-3.91 (m, 2H),2.80-2.76 (m, 2H). MS (ESI) m/e [M+1]⁺ 427.9.

Compound 53:7-(3-Chloropropanoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide

7-Acryloyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide(40 mg, 0.09 mmol) was suspended in Sat. HCl (gas)/dioxane (50 mL), thenthe mixture was stirred RT for about 1.5 hr, and concentrated todryness. The residue was suspended into 2 mL of MeOH and 2 mL of water.The organic layer was discarded, aqueous layer was lyophilized to get 40mg (90%) of7-(3-chloropropanoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide as an off-white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.79-11.76 (m, 1H), 7.68 (d, J=8.6 Hz, 2H),7.43 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H),7.10-7.04 (m, 4H), 4.71-4.70 (m, 2H), 3.85-3.79 (m, 4H), 3.02 (t, J=6.4Hz, 2H), 2.79-2.69 (m, 2H). MS (ESI) m/e [M+1]⁺ 463.8, 465.8.

Compound 54 and 55:(E)-7-(4-(Dimethylamino)but-2-enoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide and7-Acetyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide

A mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (147mg, 0.88 mmol), HATU (611 mg, 1.6 mmol) and TEA (328 mg, 3.2 mmol) in 50mL of DCM was stirred at RT for about 2 hr before2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide (300 mg, 0.8 mmol) wasadded. The mixture was stirred at RT overnight. TLC and LCMS analysisshowed that starling material was consumed. To the reaction were added100 mL of water and 50 mL of DCM. Aqueous phase was further extractedwith 50 mL of DCM. The combined organic layers were washed with brine,dried over Na₂SO₄, concentrated to get crude product which waschromatographed on 5 g of silica gel using DCM/MeOH (20/1 to 10/1) aseluant to afford 145 mg (37%) of (E)-7-(4-(dimethylamino)but-2-enoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide, which was dried bylyophilization. ¹H NMR (400 MHz, DMSO-d₆) at 80° C.) δ 11.52 (s, 1H),7.69 (d, J=8.6 Hz, 2H), 7.42 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H),7.16 (t, J=7.6 Hz, 1H), 7.12-6.99 (m, 4H), 6.78-6:56 (m, 2H), 6.22 (s,2H), 4.75 (s, 2H), 3.89 (t, J=5.6 Hz, 2H). 3.12 (d, J=5.6 Hz, 2H),2.80-2.72 (m, 2H), 2.22 (s, 6H). MS (ESI) m/e [M+1]⁺ 484.9.

7-Acetyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamidewas prepared as a byproduct due to some of HOAc residue in the laststep. ¹H NMR (400 MHz, DMSO-d₆) δ 11.77-11.73 (m, 1H), 7.70-7.66 (m,2H), 7.43 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz,1H), 7.13-6.94 (m, 4H), 4.68 (s, 2H), 3.83-3.76 (m, 2H), 2.82-2.77 (m,2H), 2.14 (s, 3H). MS (ESI) m/e [M+1]⁺ 416.

Compound 56:7-(2-Cyanoacetyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide

The desired compound was prepared from2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide and 2-cyanoacetic acidaccording to the procedure similar to that for compound 54. ¹H NMR (400MHz, DMSO-d₆ at 80° C.) δ 11.55 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.41(d, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H),7.11-6.93 (m, 4H), 6.22 (br s, 2H), 4.68 (s, 2H), 4.14 (s, 2H),3.86-3.79 (m, 2H), 2.84-2.73 (m, 2H). MS (ESI) m/e [M+1]⁺ 440.9.

Compound 57:7-(3-Dimethylamino)propanoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamidetrifluoroacetate

To a solution of7-acryloyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide (6 mg, 0.014 mmol) in 5mL of MeOH at RT was added NaOMe (15 mg, 0.28 mmol) followed bydimethylamine hydrochloride (12 mg, 014 mmol), then the mixture wasstirred at 50° C. overnight. After cooling down to RT, the mixture wasconcentrated. The residue was purified by pre-HPLC eluting from 0% to60% CH₃CN in H₂O. Fractions containing the desired product were combinedand lyophilized overnight to give 2.5 mg (35%) of6-(3-(dimethylamino)propanoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ 11.84-11.82 (m, 1H), 9.55 (s, 1H), 7.69-7.66(m, 2H), 7.44 (d, J=7.6 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.6Hz, 1H), 7.10-7.04 (m, 4H), 4.75-4.72 (m, 2H), 3.87-3.82 (m, 2H),3.02-3.00 (m, 2H), 2.84-2.78 (m, 2H), 2.77 (s, 6H), 2.71-2.68 (m, 2H).MS (ESI) m/e [M+1]⁺ 472.9.

Compound 58:7-(But-2-enoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide

The desired compound was prepared from2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide and but-2-enoic acidaccording to the procedure similar to that for compound 54. ¹H NMR (400MHz, DMSO-d₆) δ 11.78-11.71 (m, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.46-7.39(m, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.11-7.04 (m, 4H), 6.73-6.63 (m, 2H),4.80-4.71 (m, 2H), 3.90 (s, 2H), 2.76-2.70 (m, 2H), 1.88-1.86 (m, 3H).MS (ESI) m/e [M+1]⁺ 441.9,

Compound 59 and 60:(E)-7-(3-Cyanoallyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide and(Z)-7-(3-Cyanoallyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide

To a solution or2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide(100 mg, 0.268 mmol) in 10 mL of acetone at RT was added K₂CO₃ (140 mg,1.07 mmol). After stirring at RT for 2 hr, 4-bromobut-2-enenitrile (40mg, 0.268 mmol) in 2 mL of acetone was added and stirred at RTovernight. The mixture was then partitioned between EA (50 mL) and water(100 mL). The aqueous phase was further extracted with 50 mL of EA. Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated to get crude product which was further purified by pre-TLC(DCM/MeOH=15/1) to afford 7 mg (6%) of(E)-7-(3-cyanoallyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide as a light yellow solid.¹H NMR (400 MHz, CDCl₃) δ 10.45 (s, 1H), 7.5 (d, J=8.4 Hz, 2H),7.42-7.30 (m, 2H), 7.16 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 7.06(d, J=7.6 Hz, 2H), 6.76 (dt, J=16.3,4.6 Hz, 1H), 5.67 (d, J=16.3 Hz,1H), 5.62 (s, 2H), 3.82 (s, 2H), 3.41 (d, J=4.6 Hz, 2H), 2.95-2.75 (m,4H). MS (ESI) m/e [M+1]⁺ 439.9.

4 mg (3.4%) of(Z)-7-(3-cyanoallyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide as a light yellow solid.¹H NMR (400 MHz, CDCl₃) δ 10.22 (s, 1H), 7.60 (d, J=8.4 Hz, 2H),7.41-7.33 (m, 2H), 7.16 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.4Hz, 2H), 7.06(d, J=7.6 Hz, 2H), 6.70-6.59 (m, 1H), 5.58 (s, 2H), 5.53 (d, J=11.2 Hz,1H), 3.85 (s, 2H), 3.64 (d, J=6.4 Hz, 2H), 2.99-2.80 (m, 4H). MS (ESI)m/e [M+1]⁺ 439.9.

Example 22 Synthesis of Compounds 61 to 64 Compound 61:2-(4-Phenoxyphenyl)-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide

Step 1: 3-Bromo-4-hydrazinylpyridine

A mixture of 3-bromo-4-chloropyridine (5 g, 0.026 mol) and hydrazinehydrate (80% in water, 80 mL) in dioxane (100 mL) was stirred at 100° C.overnight. After cooling down to RT, the mixture was concentrated. Theresidue was partitioned between 300 mL of EA and 300 mL of aq. sat.NH₄Cl. The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to get crude product which was suspended in 30mL of cold isopropyl alcohol and filtered. The collected solid was driedin air to get 4.2 g (87%) of 3-bromo-4-hydrazinylpyridine as a whitesolid. ¹H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.07 (d, J=5.6 Hz, 1H),7.37 (s, 1H), 7.01 (d, J=5.6Hz, 1H), 4.36 (s, 2H).

Step 2:5-Amino-1-(3-bromopyridin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile

A mixture of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (7.3 g,0.026 mol) and 3-bromo-4-hydrazinylpyridine (4.2 g, 0.022 mol) inethanol (300 mL) was stirred at reflux under N2 overnight. The reactionwas cooled to RT slowly and stirred at RT for about 4 hr till solidprecipitated. The solid was filtered, collected and washed with hexaneto gel 3.38 g (35%) of5-amino-1-(3-bromopyridin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrileas a light yellow solid. MS (ESI) m/e [M+1]⁺ 431.8, 433.8.

Step 3:5-Amino-1-(3-bromopyridin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

The desired compound was prepared from5-amino-1-(3-bromopyridin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrileaccording to the procedure similar to step 3 for compound 51. MS (ESI)m/e [M+1]⁺ 449.8, 451.8.

Step 4:2-(4-Phenoxyphenyl)-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide

A mixture of5-amino-1-(3-bromopyridin-4-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(3.96 g, 8.8 mmol), Cul (836 mg, 4.4 mmol), N¹,N²-dimethylethane-1,2-diamine (77 mg, 0.88 mmol), K₃PO₄ (5.59 g, 26.4mmol) in 100 mL of DMF was stirred at 100° C. under N₂ or 2 hr, untilTLC showed that most of starting material was consumed. After coolingdown to RT, the mixture was filtered and concentrated. The residue waschromatographed on 30 g of silica gel using DCM/ MeOH (20/1 to 10/1) aseluant to afford 3.2 g (99%) of 2-(4-Phenoxyphenyl)-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide as a tan solid. ¹H NMR(400 MHz, DMSO-d₆) δ 12.63 (br s, 1H), 8.85 (s, 1H), 8.46 (s, 1H), 7.96(d, J=4.6 Hz, 1H), 7.81 (d, J=8.6 Hz, 2H), 7.45 (d, J=7.6 Hz, 1H), 7.43(d, J=7.6 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.14-7.09 (m, 4H). MS (ESI)m/e [M+1]⁺ 369.9.

Compound 62:2-(4-Phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide

Step 1:6-Benzyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide

To a suspension of2-(4-phenoxyphenyl)-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carbox-amide(2.46 g, 0.0067 mol) in 150 mL of THF was added benzyl bromide (1.14 g,0.0067 mol) dropwise, then the mixture was stirred at 65° C. overnight.After cooling down to RT, the mixture was concentrated, the residue wassuspended in 150 mL of MeOH, NaBH₄ (10 g, 0.26 mol) was addedportionwise. The mixture was stirred at RT overnight. To the reactionwas added 200 mL of water followed by 200 mL of DCM. The aqueous phasewas further extracted with 100 mL of DCM. The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated to get thecrude product which was chromatographed on 10 g of silica gel usingDCM/MeOH (200/1 to 80/1) as eluant to afford 0.786 g (26%) of6-benzyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide as a tan foam. MS (ESI)m/e [M+1]⁺ 463.9.

Step 2:2-(4-Phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide

A mixture of 6-benzyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide (640 mg, 0.00138 mol)and 10% w/w Pd/C (700 mg) in 60 mL of MeOH was stirred at RT under 1 atmof H₂ overnight. TLC and LCMS analysis showed starting material wasconsumed. The reaction was filtered, filtrate was concentrated to get397 mg (77%) of 2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide. ¹H NMR (400 MHz,CD₃OD-d₄) δ 7.65-7.55 (m, 2H), 7.43-7.33 (m, 2H), 7.18-7.12 (m, 1H),7.11-6.99 (m, 4H), 4.18 (s, 2H), 3.44 (t, J=5.8 Hz, 2H), 3.01 (t, J=5.8Hz, 2H). MS (ESI) m/e. [M+1]⁺ 373.9.

Compound 63:6-Acryloyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide trifluoroacetate

The desired compound was prepared from2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide and acryloyl chlorideaccording to the procedure similar to that for compound 8. ¹H NMR (400MHz, DMSO-d₆) δ 11.79 (s, 1H), 7.73 (d, J=8.6 Hz. 2H), 7.50 (d, J=7.6Hz. 1H), 7.48 (d, J=7.6 Hz. 1H), 7.24 (t, J=7.6 Hz, 1H), 7.17-7.11 (m,4H), 7.06-6.98 (m, 1H), 7.22-6.26 (m, 1H), 5.84-5.82 (m, 1H), 4.72 (s,2H). 4.00-3.97 (m, 2H), 2.94-2.90 (m, 2H). MS (ESI) m/e [M+1]⁺ 427.9.

Compound 64:(E)-6-(4-(Dimethylamino)but-2-enoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamidetrifluoroacetate

The desired compound was prepared from2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide and(E)-4-(dimethylamino)but-2-enoic acid hydrochloride according to theprocedure similar to that for compound 54. ¹H NMR (400 MHz, DMSO-d₆) δ11.82-11.74 (m, 1H), 10.06 (br s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.43 (d,J=7.6 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.10-7.05(m, 4H), 6.74-6.54 (m, 2H), 4.66 (s, 2H), 3.99-3.86 (m, 4H), 2.88-2.76(m, 2H), 2.78 (s, 6H). MS (ESI) m/e [M+1]⁺ 484.9.

Example 23 Synthesis of Compounds 65-67 Compound 65:7-Nitro-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamide

Step 1: (2-Bromo-5-nitrophenyl)hydrazine

To a suspention of 2-bromo-5-nitroaniline (1 g, 4.6 mmol) in conc. HCl(10 mL) at 0°C. was slowly added a solution of NaNO₂ (382 mg, 5.5 mmol)in water (1.5 mL). Then, the mixture was stirred at 0° C. for 3 hr untilTLC and LCMS analysis showed that most of 2-bromo-5-nitroaniline wasconsumed. SnCl₂ (1.90 g, 10 mmol)in conc. HCl (3 mL) was slowly added.The mixture was then stirred at RT for 2 hr before re-cooled to 0° C.Then, the PH was adjusted with sat. aq. NaHCO₃ to 7-8. The mixture wasextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated to gelcrude product which was further chromatographed on 10 g of silica gelusing PE/EA (20/1 to 4/1) as eluant to afford 560 mg (51 %) of(2-bromo-5-nitrophenyl)hydrazine as a orange solid. 1H NMR (400 MHz,DMSO-d6) δ 7.89 (d, J=2.8 Hz, 1H), 7:60 (d, J=8.6 Hz, 1H), 7.29 (dd,J=2.8, 8.6 Hz, 1H), 7.04 (s, 1H), 4.38 (s, 2H). MS (ESI) m/e [M+1]⁺ 232,234.

Step 2:5-Amino-1-(2-bromo-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile

To a solution of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (392mg, 1.42 mmol) in ethanol (30 mL) was added(2-bromo-5-nitrophenyl)hydrazine (300 mg, 1.29 mmol) in one portion,then the mixture was stirred at 70° C. under N₂ overnight. The mixturewas concentrated to dryness and chromatographed on 5 g of silica gelusing PE/EA (10/1 to 2/1) as eluant to afford 128 mg (21%) of5-amino-1-(2-bromo-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrileas a yellow solid. MS (ESI) m/e [M+1]⁺ 476, 478.

Step 3:5-Amino-1-(2-bromo-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

A mixture of 5-amino-1-(2-bromo-5-nitrophenyl)-3-(4,-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (137 mg, 0.287 mmol) in phosphorous acid (85 wt.% in H₂O, 10 mL) was stirred at 100° C. for 1 hr, until TLC and LCMSanalysis showed that most of starting material was consumed. Thereaction Was cooled to room temperature and partitioned between water(40 mL) and EA (40 mL), Organic layer was separated from aqueous layer.The aqueous phase was then extracted with EA (20 mL). The combinedorganic layers were washed with brine (50 mL), dried over Na₂SO₄ andconcentrated to get the crude product (149 mg) which was used in nextstep without further purification. MS (ESI) m/e [M+1]⁺ 494, 496.

Step 4:7-Nitro-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamide

A mixture of5-amino-1-(2-bromo-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(149 mg, 0.3 mmol, crude), Cul (5.7 mg, 0.03 mmol), N¹,N²-dimethylethane-1,2-diamine (3 mg, 0.03 mmol), K₃PO₄ (64 mg, 0.3 mol)in 15 mL of DMF was stirred at 60°C. under N₂ for 5 hr, until TLCanalysis showed that most of starting material was consumed. Thereaction was cooled to RT. The solvent was removed under reducedpressure. The residue was chromatographed on 5 g of silica gel usingDCM/MeOH (200/1 to 20/1) to afford 62 mg (52%) of7-nitro-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamideas a tan solid. MS (ESI) m/e [M+1]⁺ 414.

Compound 66: 7-Amino-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamide

To a solution of 7-nitro-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-6]pyrazole-3-carboxamide (9 mg, 0.022 mmol) in 3 mL of HOAc was added zincpowder (14 mg, 0.22 mmol). Then the mixture was stirred at RT for 20min, until TLC and LCMS analysis showed that most of starting materialwas consumed. The reaction solid was filtered off. The filtrate wasconcentrated, suspended in 10 mL of EA and filtered. The filtrate wasconcentrated to get the product as a white solid (4 mg, 50%). ¹H NMR(400 MHz, CD₃OD-d₄) δ 7.60 (d, J=8.6 Hz, 2H), 7.32 (d, J=8.0 Hz, 1H),7.30 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (s, 1H), 7.08 (t,J=8.0 Hz, 1H), 7.05-6.95 (m, 4H), 6.79 (dd, J=1.6, 8.4 Hz, 1H). MS (ESI)m/e [M+1]⁺ 384.

Compound 67:7-Acrylamido-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamide

To a solution of 7-amino-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamide (45 mg, 0.11 mmol) in 10 mL of DCM at 0° C. wasadded TEA (36 mg, 0.35 mmol). Acryloyl chloride (11 mg, 0.12 mmol) in 2mL of DCM was added dropwise over a period of 20 min. The mixture wasstirred until TLC and LCMS analysis showed that most of startingmaterial was consumed. The mixture was then partitioned between water.(50 mL) and DCM (20 mL), extracted with additional 20 mL of DCM. Thecombined organic layer was washed with brine, dried over Na₂SO₄,concentrated and purified by Pre-TLC (DCM/MeOH=20/1) to get 4 mg (7.8%)of7-acrylamido-2-(4-phenoxyphenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxamideas a grey solid. ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.25 (s, 1H). 7.61 (d,J=8.4 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.32 (d,J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.08 (t, J=7.6 Hz, 1H), 7.05-6.90(m, 4H), 6.42-6.25 (m, 2H), 5.69 (dd, J=9.6, 1.9 Hz, 1H). MS (ESI) m/e[M+1]⁺ 438.

Example 24 Synthesis of compounds 68-69 Compound 68:8-Amino-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

Step 1: (2-Fluoro-4-nitrophenyl)methanol

To a solution of 2-fluoro-4-nitrobenzaldehyde (1.0 g, 5.92 mmol) inCH₃OH (10 mL) was added NaBH₄ (814 mg, 22 mmol). After stirring at RTfor 15 min, the mixture was concentrated. The residue was partitionedbetween 100 mL of EA and 100 mL of brine. The combined organic layerswere washed with brine (100 mL×2), dried over Na₂SO₄, and concentratedto afford 1.0 g of (2-fluoro-4-nitrophenyl) methanol (99%) as a redsolid. MS (ESI) m/e [M+1]⁺ 172.0.

Step 2: 2-(2-Fluoro-4-nitrobenzyloxy)-tetrahydro-2H-pyran

To a solution of (2-fluoro-4-nitrophenyl)methanol (755 mg, 4.42 mmol) in10 mL of DCM was added TsOH (100 mg, 0.13 mmol) and DHP (408 mg, 4.86mmol). After stirring at RT for 16 hr, the mixture was concentrated. Theresidue was partitioned between 100 mL of EA and 100 mL of brine. Thecombined organic layers were washed with brine (100 mL×2), dried overNa₂SO₄, concentrated and purified by chromatography column on silica gel(elution with PE/EA) to afford 900 mg (80%) of2-(2-fluoro-4-nitrobenzyloxy)-tetrahydro-2H-pyran as a colorless oil. ¹HNMR (400 MHz, DMSO-d₆) δ 8.34 (dd, J=3,0, 6.2 Hz, 1H), 8.26-8.30 (m,1H), 7.53 (t, J=9.2 Hz, 1H), 4.82-4.76 (m, 2H), 4.62 (d, J=12.0 Hz, 1H),3.80-3.74 (m, 1H), 3.52-3.47 (m, 1H), 1.76-1.64 (m, 2H) and 1.58-1.45(m, 4H).

Step 3:5-Amino-1-(5-nitro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(27.6 mg, 0.1 mmol) in DMF (3 mL) and CH₃CN (5 mL) was added2-(2-fluoro-4-nitrobenzyloxy)-tetrahydro-2H-pyran (25.5 mg, 0.1 mmol)and K₂CO₃ (27.6 mg, 0.2 mmol). After stirring at 80° C. under N₂ for 16hr, the mixture was concentrated and recrystallized with PE/EA to afford40 mg (80%) of5-amino-1-(5-nitro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamideas a yellow solid. MS (ESI) m/e [M+1]⁺ 512.2.

Step 4:5-Amino-1-(2-(hydroxymethyl)-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

To a solution of5-amino-1-(5-nitro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)-3-(4-phenoxyphenyl)-3H-pyrazole-4-carboxamide(690 mg, 1.3 mmol) in 10 mL of CH₃CN was added hydrochloric acid (3 mL).After stirring at RT for 15 min, the mixture was concentrated to afford550 mg (95%) of5-amino-1-(2-(hydroxylmethyl)-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamideas a yellow solid.

Step 5:5-Amino-1-(2-formyl-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide

To a solution of5-amino-1-(2-(hydroxymethyl)-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(550 mg, 1.24 mmol) in 20 mL of DCM was added MnO₂ (500 mg, 5.75 mmol).After stirring at RT for 16 hr, the mixture was filtered. The filtratewas concentrated to afford 400 mg (73%) of5-amino-1-(2-formyl-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamideas a yellow solid.

Step 6:8-Nitro-2-(4-phenoxyphenyl)pyrazolo[1,5-a]quinazoline-3-carboxamide

To a solution of5-amino-1-(2-formyl-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(400 mg, 0.9 mmol) in 5 mL of CH₃OH and 5 mL of DCM was added HOAc (1drops). After stirring at RT for 16 hr, the mixture was concentrated andpurified by chromatography column on silica gel eluting with PE/EA toafford 240 mg (63%) of 8-nitro-2-(4-phenoxyphenyl) pyrazolo[1,5-a]quinazoline-3-carboxamide as a yellow solid. MS (ESI) m/e [M+1]⁺425.8.

Step 7:8-Nitro-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3carboxamide

To a solution of8-nitro-2-(4-phenoxyphenyl)pyrazolo[1,5-a]quinazoline-3-carboxamide (240mg, 0.57 mmol) in 10 mL of EtOH and 10 mL of DCM was added NaBH₄ (86 mg,2.26 mmol) at RT. After stirring at RT for 20 min, 10 mL of water wasadded. The mixture was concentrated. 5 mL of water was added andfiltered. The cake was washed with tert-Butyl methyl ether (30 mL) anddried to afford 200 mg (83%) of8-nitro-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide as a yellow solid. MS (ESI) m/e [M+1]⁺427.9.

Step 8:8-Amino-2-(4-phenoxyphenyl)4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamideand 8-amino-2-(4-phenoxyphenyl)pyrazolo[1,5-a]quinazoline-3-carboxamide

To a solution of8-nitro-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide(200 mg, 0.47 mmol) in 30 mL of CH₃OH and 30 mL of DCM was added 10% w/wPd/C (100 mg). After stirring at RT for 1 hr, the mixture was filtered.The filtrate was concentrated to afford 130 mg (70%) of crude8-amino-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamideand 8-amino-2-(4-phenoxyphenyl) pyrazolo[1,5-a]quinazoline-3-carboxamideas a yellow solid. MS (ESI) m/e [M+1]⁺ 398.0, 395.9.

Step 9:8-Amino-2-(4-phenoxyphenyl)-4,5-dihydropyrazoIo[1,5-a]quinazoline-3-carboxamide

To a solution of the mixture of 8-amino-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide and 8-amino-2-(4-phenoxyphenyl)pyrazolo[1,5-a]quinazoline-3-carboxamide (130 mg, 0.33 mmol) in 10 mL ofDCM and 10 mL of CH₃OH was added NaBH₄ (277 mg, 3.3 mmol). Afterstirring at RT for 15 min, 50 mL of water was added. The mixture wasconcentrated and filtered. The cake was washed with water, (50 mL×2) toafford 60 mg (46%) of8-amino-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamideas a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (d, J=8.0 Hz, 2H),7.44 (d, J=7.6 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H),7.18 (t, J=7.6 Hz, 1H), 7.14-7.16 (m,4H), 6.81 (s, 1H), 6.52 (d, J=8.0Hz, 1H), 6.43 (s, 1H), 5.16 (s, 2H) and 4.37 (s, 2H). MS (ESI) m/e[M+1]⁺ 397.9.

Compound 69:8-Acrylamido-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The desired product was prepared from compound 68 and acryloyl chlorideusing the procedure similar to that for compound 8. ¹H NMR (400 MHz,DMSO-d₆) δ 10.26 (s, 1H), 7.39-7.63 (m, 4H), 7.52 (d, J=8.8 Hz, 1H),7.45 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H). 7.19 (t, J=8.0 Hz, 1H),7.14-7.07 (m, 4H), 7.01 (s, 1H), 6.44(dd, J=10.4, 17.0 Hz, 1H), 6.26(dd,J=1.6, 17.0 Hz, 1H), 5.77 (dd, J=1.6, 10.4 Hz, 1H) and 4.51 (s, 2H). MS(ESI) m/e [M+1]⁺ 451.9.

Example 25 Synthesis of Compounds 70-72 Compound 70:8-Nitro-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide

Step 1: 2-(2-Fluoro-5-nitrophenyl)ethanol

To a solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (2.0 g, 10 mmol)in THF (50 mL) was added borane dimethyl sulfide complex solution (4.0g, 25 mmol). The reaction was warmed to 60° C. stirred for about 12 hr.After cooling down to RT, CH₃OH (20 mL) was slowly added to thereaction, concentrated under reduced pressure to remove solvent. Theresidue was purified by column chromatography on silica gel (200-300mesh, PE/EA=2/1) to afford the product as a colorless oil (1.6 g,86.1%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (t, J=3.2, 6.4 Hz, 1 H),8.19-8.14 (m, 1 H), 8.45 (t, J=9.2 Hz, 1 H), 4.80 (t, J=5.6 Hz, 1 H),3.66 (dt, J=5.6, 6.4 Hz, 1 H), 2.86 (t, J=6.4 Hz, 2 H). MS (ESI) m/e[M+1]⁺ 186.

Step 2:8-Nitro-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide

To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(30 mg, 0.10 mmol) in DMF (5.0 mL) was added K₂CO₃ (28 mg, 0.20 mmol),followed by 2-(2-fluoro-5-nitrophenyl) ethanol (37 mg, 0.20 mmol). Themixture was warmed to 80° C. stirred for about 16 hr. After cooling downto RT, the mixture was concentrated under reduced pressure. The residuewas partitioned between ethyl acetate (15 mL) and water (15 mL), theaqueous was extracted with ethyl acetate (3×10 mL). The combined organicphases were washed brine (10 mL), dried over Na₂SO₄, filtered,concentrated and purified by Pre-TLC (DCM/CH₃OH=20/1) to afford theproduct about 5.0 mg (11.1%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (t, J=4.0Hz, 1 H), 8.28 (d, J=2.8 Hz, 1 H), 8.22 (dd, J=2.8, 9.2 Hz, 1 H), 8.12(d, J 9.2 Hz, 1 H), 7.64-7.60 (m, 2 H), 7.45-7.41 (m, 2 H), 7.22-7.17(m, 1 H), 7.14-7.09 (m, 4 H), 3.72-3.65 (m, 2 H), 3.29-3.24 (m, 2 H). MS(ESI) m/e [M+1]⁺ 442.

Compound 71: 8-Amino-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide

To the solution of8-nitro-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide (80 mg, 0.18 mmol) in ethanol (20mL) was added 10% w/w Pd/C (20 mg), the reaction was stirred at RT underH₂ for about 3 hr. Filtered and washed with CH₃OH (20 mL), the filtratewas concentrated under reduced pressure, the residue was purified byPre-TLC (DCM/CH₃OH=20/1) to afford the product as a white solid (20 mg,26.8%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.73-7.69 (m, 1H), 7.59-7.55 (m,2H), 7.45-7.40 (m, 3H), 7.21-7.16 (m, 1H), 7.13-7.07 (m, 4H), 6.59-6.54(m, 1H), 6.50-6.47 (m, 1H), 5.70-5.40 (br s, 2H), 3.64-3.59 (m, 2H),2.99-2.94 (m, 2H). MS (ESI) m/e [M+1]⁺ 412.

Compound 72: 8-Acrylamido-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide

The desired compound was prepared from compound 71 and acryloyl chlorideaccording to the procedure similar to that for compound 8. ¹H NMR (400MHz, DMSO-d₆) δ 10.25 (s, 1H), 7.95 (t, J=4.0 Hz, 1H), 7.76 (d, J=8.8Hz, 1H), 7.65-7.58 (m, 4H), 7.46-7.41 (m, 2H), 7.21-7.17 (m, 1H),7.13-7.08 (m, 4H), 6.44(dd, J=10.0, 16.8 Hz, 1H), 6.27 (dd, J=2.0, 16.8Hz, 1H), 5.77 (dd, J=2.0, 10.0 Hz, 1H), 3.68-3.65 (m, 2H), 3;05-3.03 (m,2H). MS (ESI) m/e [M+1]⁺ 466.

Example 26 Synthesis of Compounds 73-75 Compound 73:8-Nitro-5-oxo-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide

Step 1: Methyl 2-(2-fluoro-5-nitrophenyl)acetate

To a solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (1.0 g, 5.0 mmol)in CH₃OH (20 mL) was added con. H₂SO₄ (0.50 mL). the reaction was warmedto 80° C. and stirred for about 3 hr. After cooling down to RT, thereaction was poured into water (20 mL) and concentrated to remove CH₃OH.The aqueous was extracted with ethyl acetate (2×20 mL), the combinedorganic phases were washed brine (10 mL), dried over Na₂SO₄. filteredand concentrated to afford the product about 1.0 g (93.4%) as acolorless oil. MS (ESI) m/e [M+1]⁺ 214.0.

Step 2:8-Nitro-5-oxo-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide

To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide(30 mg, 0.10 mmol) in DMF (5 mL) was added K₂CO₃ (28 mg, 0.20 mmol) andmethyl 2-(2-fluoro-5-nitrophenyl) acetate (21 mg, 0.10 mmol). Themixture was warmed to 80° C. stirred for about 16 hr. After cooling downto RT, the mixture was concentrated under reduced pressure to removesolvent. The residue was portioned with DCM (10 mL) and water (10 mL).the aqueous was extracted with DCM (2×10 mL), the combined organicphases were washed sat. Sodium chloride (10 mL), dried over anhydrousSodium sulfate, filtered, concentrated and purified by pre-TLC(DCM/CH3OH=20/1) got the product about 10 mg (21.9%). ¹H NMR (400 MHz,DMSO-d₆) δ 10.66 (br s, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.37 (dd, J=2.6,9.2 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.65-7.53(br s, 2H), 7.45-7.40 (m, 2H), 7.22-7.16 (m, 1H), 7.12-7.05 (m, 4H),3.92 (s, 2H). MS (ESI) m/e [M+1]⁺ 456.1.

Compound 74:8-Amino-5-oxo-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide

Compound 74 was prepared from8-nitro-5-oxo-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide according to theprocedure similar to that for compound 71. ¹H NMR (400 MHz, CD₃OD-d₄) δ7.72-7.67 (m, 2H), 7.52 (d, J=8.8 Hz, 1H), 7.42-7.37 (m, 2H), 7.19-7.14(m, 1H), 7.11-7.05 (m, 4H), 6.80 (dd, J=2.6, 8.8 Hz, 1H), 6.69 (d, J=2.6Hz, 1H), 3.59 (s, 2H). MS (ESI) m/e [M+1]⁺ 426.1.

Compound 75:8-Acrylamido-5-oxo-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide

Compound 75 was prepared from8-amino-5-oxo-2-(4-phenoxyphenyl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,3]diazepine-3-carboxamideand acryloyl chloride according to the procedure similar to that forcompound 8. ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.85-7.79 (m, 3H), 7.75-7.71(m, 2H), 7.43-7.37 (m, 2H), 7.20-7.14(m, 1H), 7.12-7.06 (m, 4H),6.50-6.35 (m, 2H), 5.81 (dd, J=2.6, 9.0 Hz, 1H), 3.75 (s, 2H). MS (ESI)m/e [M+1]⁺ 480.1. Example 27 Synthesis of Compounds 76-79 Compound 76:7-Nitro-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (220mg, 0.75 mmol), methyl 2-chloro-5-nitrobenzoate (160 mg, 0.75 mmol) andK₂CO₃ (155 mg, 1.13 mmol) in DMF (10 mL) was heated to 80° C. for 16 hrunder N₂. The reaction was poured into water (30 ml), and extraced withethyl acetate (20 mL×3). The combined organic layers were dried overNa₂SO₄, concentrated under reduced pressure to a residue, which waspurified by a silica gel column eluting with 10% to 50% EA in PE toafford 85 mg (27.3%) of 7-nitro-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide as a yellow solid.MS (ESI, m/e) [M+1]⁺ 442.1.

Compound 77:7-Amino-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

Compound 77 was prepared from7-nitro-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide according to the proceduresimilar to that for compound 71. ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (brs, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.71 (d, J=6.8 Hz, 2H), 7.36-7.42 (m,2H), 7.27 (s, 1H), 7.02-7.17 (m, 6H), 5.62 (s, 2H). MS (ESI, m/e) [M+1]⁺412.1.

Compound 78:7-Acrylamido-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

Compound 78 was prepared from7-amino-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide and acryloyl chloride according to theprocedure similar to that for compound 8. ¹H NMR (400 MHz, DMSO-d₆) δ11.37,(s, 1H), 10.77 (s, 1H), 8.65 (s, 1H), 8.24 (d, J=8 Hz, 1H), 8.15(d, J=8 Hz, 1H), 7.85 (d, J=7.6 Hz, 2H), 7.48-7.52 (m, 2H), 7.2-7.15 (m,5H), 6.57 (dd, J=9.2, 18.0 Hz, 1H), 6.37 (d, J=18.0 Hz, 1H), 5.87 (d,J=9.2 Hz, 1H), MS (ESI, m/e) [M+1]⁺ 466.1. Compound 79:8-Amino-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The desired product was prepared from methyl 2-chloro-4-nitrobenzoateand 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide using theprocedures similar to those for compound 76 and 77. ¹H NMR (400 MHz,DMSO-d₆) δ 10.61 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.0 Hz,2H), 7.44-7.36 (m, 2H), 7.19-7.02 (m, 6H), 6.64 (d, J=8.4 Hz, 1H), 6.55(br s, 2H). MS (ESI, m/e) [M+1]⁺ 412.1.

Example 28 Synthesis of Compounds 80-81 Compound 80:5-Oxo-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: tert-Butyl4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)piperidine-1-carboxylate

To a slimed mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylicacid (1.15 g, 5 mmol) and DMAP (61 mg, 0.5 mmol) in DCM (50 mL) wasadded DCC (1.14 g, 5.5 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (0.8g, 5.5 mmol). The resulting mixture was stirred at rt for 16 hr andfiltered. The filtrate was concentrated under vacuum to affordtert-butyl4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)piperidine-1-carboxylate 2 g (crude) as a yellow oil, which was used inthe next step without further purification. MS (ESI) m/e [M+23]⁺ 378.1.

Step 2: tert-Butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

A solution of tert-butyl4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonyl)piperidine-1-carboxylate(2 g, 5.63 mmol) in ethanol (50 ml) was refluxedfor 20 h, then the solvent was removed under vacuum, and the residue waspurified by silica gel chromatography eluted with DCM to afford 0.5 g(30%) of tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateas a reddish oil. MS (ESI) m/e [M+23]⁺ 322.2.

Step 3:5-Oxo-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (412mg, 1.4 mmol) and tert-butyl4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (420 mg, 1.4 mmol)in HOAc (20 mL) was stirred at 90° C. for 16 hr. The solvent was removedunder vacuum, and the residue was partitioned between aq. NaHCO₃ andethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated under vacuum. The residue was purified byPre-HPLC eluting from 25% to 90% CH₃CN in 0.1% TFA in H₂O. Fractionscontaining the desired product were combined and lyophilized overnightto afford 5-oxo-2-(4-phenoxyphenyl)-7-(piperidin4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide(0.3 g, 50%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (br s,1H), 8.68-8.65 (m, 1H), 8.42-8.39 (m, 1H), 7.74 (d, J=8.4 Hz, 2H),7.47-7.41 (m, 2H), 7.22-7.18 (m, 1H), 7.14-7.09 (m, 4H), 5.72 (s, 1H),3.50-3.35 (m, 2H), 3.17-3.06 (m, 1H), 3.01-2.87 (m, 2H), 2.15-2.05 (m,2H), 1.83-1.72 (m, 2H), MS (ESI) m/e [M+1]⁺ 430.1.

Compound 81:5-Oxo-2-(4-phenoxyphenyl)-7-(1-propionylpiperidin-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from compound 80 and acryloyl chlorideusing the procedure similar to that for compound 8.¹H NMR (400 MHz,DMSO-d₆) δ 11.74 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.47-7.41 (m, 2H),7.20 (t, J=7.2 Hz, 1H), 7.12-7.09 (m, 4H), 6.85 (dd, J=10.6, 16.6 Hz,1H), 6.12(dd, J=2.4, 16.6 Hz, 1H), 5.76 (s, 1H), 5.69 (dd, J=2.4, 10.6Hz, 1H), 4.63-4.58 (m, 1H), 4.24-4.20 (m, 1H), 3.15-3.05 (m, 2H),2.69-2.63 (m, 1H), 1.99-1.91 (m, 2H), 1.61-1.58 (m, 2H). MS (ESI) m/e[M+1]⁺ 483.9.

Example 29 Synthesis of Compounds 82-83 Compound 82:2-Oxo-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carboxamide

Step 1:1′-Benzyl-2-oxo-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carbonitrile

A mixture of ethyl 1-benzyl-4-hydrazinylpiperidine-4-carboxylatehydrochloride (350 mg, 1.0 mmol),2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (276 mg, 1.0 mmol)and K₂CO₃ (414 mg, 3.0 mmol) in MeOH (20 mL) was heated to reflux for 16hr. The mixture was filtered and the filtrate was concentrated to givethe crude product (280 mg, 58.9%) as a yellow solid. MS (ESI, m/e)[M+1]⁺ 475.9.

Step 2:1′-Benzyl-2-oxo-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carboxamide

A solution of1′-benzyl-2-oxo-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carbonitrile(200 mg, 0.42 mmol) in H₃PO₄ (15 mL) was heated to 120° C. for 2 hr. Thesolution was poured to water (10 mL) and extracted with EA (10 mL×3).The combined organic layers were dried over Na₂SO₄ and concentrated togive the crude product (120 mg, 58.0%) as an off-white solid. MS (ESI,m/e) [M+1]⁺ 493.9.

Step 3:2-Oxo-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carboxamide

To a solution of1′-benzyl-2-oxo-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carboxamide (120 mg, 0.24 mmol) inMeOH (10 mL) was added 10% w/w Pd(OH);/C (5 mg) and stirred for 16 hrunder H₂. The mixture was filtered and the filtrate was concentrated togive the crude product (280 mg, 58.9%) as a yellow solid. MS (ESI, m/e)[M+1]⁺ 403.9.

Compound 83:1′-Acryloyl-2-oxo-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carboxamide

The desired product was prepared from compound 82 and acryloyl chlorideusing the procedure similar to that for compound 8. ¹H NMR (400 M Hz,DMSO-d₆) δ 11.91 (s, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.47-7.37 (m, 2H).7.25 (br s, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.08-7.02 (m, 4H), 6.88 (dd,J=16.6, 10.4 Hz, 1H), 6.80 (br s, 1H), 6.16 (d, J=16.6 Hz, 1H), 5.72(d,J=10.4 Hz, 1H), 4.32-4.14 (m, 1H), 4.12-3.99 (m, 1H), 3.97-3.81 (m, 1H),3.76-3.60 (m, 1H), 1.86-1.91 (m, 4H). MS (ESI, m/e) [M+1]⁺ 457.9.

Example 30 Synthesis of Compounds 84-85 Compound 84:6-Amino-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

S Step 1:6-Nitro-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile(83 mg, 0.3 mmol) in HOAc (2 mL) was added sodium2-nitro-1,3-dioxopropan-2-ide (47 mg, 0.3 mmol). After stirring at RTfor 1 hr, water (2 mL) was added. The mixture was partitioned between EA(25 mL) and brine (25 mL). The combined organic layers were washed withbrine (25 mL×2), dried over Na₂SO₄ and concentrated to afford 90 mg of6-nitro-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile(84%) as a yellow-solid. MS (ESI) m/e [M+1]⁺ 358.2.

Step 2:6-Nitro-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of6-nitro-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (90mg, 0.25 mmol) in 2 mL of ethanol and 2 mL of DCM was added NaBH₄ (19mg, 0.5 mmol) at RT, After stirring at RT for 30 min, 5 mL of water wasadded. The mixture was concentrated. The residue was partitioned between50 mL of DCM and 50 mL of brine. The combined organic layers were washedwith brine (50 mL×2), dried over Na₂SO₄ and concentrated to afford 50 mgof 6-nitro-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile(55%) as a yellow solid. MS (ESI) m/e [M+1]⁺ 362.1.

Step 3:6-Amino-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of6-nitro-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile(600 mg, 1.67 mmol) in 30 mL of methanol and 10 mL of DCM was added 10%w/w Pd/C (100 mg). The mixture was stirred at RT under H₂ for 2 hr andfiltered. The filtrate was concentrated and purified by chromatographycolumn on silica gel eluting with PE/EA to afford 200 mg (36%) of6-amino-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrileas a white solid. MS (ESI) m/e [M+1]⁺ 332.1.

Step 4:6-Amino-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from6-amino-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrileusing the procedure similar to step 2 for compound 2. ¹H NMR (400 MHz,DMSO-d₆) δ 7.53-7.48 (m, 2H), 7.46-7.40 (m, 2H), 7.22-7.16 (m, 1H),7.11-7.03 (m, 4H), 6.58 (br s, 1H), 4.15-4.08 (m, 1H), 3.72-3.67 (m,1H), 3.40-3.30 (m, 2H) and 3.06-2.98 (m, 1H). MS (ESI) m/e [M+1]⁺ 350.2.

Compound 85:6-Acrylamido-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from compound 84 and acryloyl chlorideusing the procedure similar to that for compound 8. ¹H NMR (400 MHz,DMSO-d₆) δ 8.47 (d, J=7.2 Hz, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.46-7.38 (m,2H), 7.18 (dd, J=7.2, 7.6 Hz, 1H), 7.09 (d, J=8.0 Hz, 2H), 7.05 (d,J=8.8 Hz, 2H), 6.67 (br s, 1H), 6.34 (dd, J=10.0, 17.2 Hz, 1H), 6.15(dd, J=2.0, 17.2 Hz, 1H), 5.63 (dd, J=2.0, 10.0 Hz, 1H), 4.32-4.40 (m,1H), 4.22 (dd, J=4.8. 12.4 Hz, 1H), 3.91 (dd, J=4.8, 12.4 Hz, 1H),3.40(m, 1H) and 3.26 (dd, J=5.2 Hz, J=12.0 Hz, 1H). MS (ESI) m/e [M+1]⁺404.1.

Example 31 Synthesis of Compound 86 Compound 86:6-(Acrylamidomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Ethyl3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate

To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile(276 mg, 1.0 mmol) in EtOH (10 mL) was added ethyl2-formyl-3-oxopropanoate (144 mg, 1.0 mmol) and HOAc (5 drops). Afterstirring at RT for 16 hr, the mixture was filtered. The cake was washedwith H₂O (10 mL×2) and dried to afford 250 mg (65%) of ethyl3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate as ayellow solid. MS (ESI) m/e [M+1]⁺ 384.9.

Step 2:6-(Hydroxymethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of ethyl3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (250mg, 0.65 mmol) in DCM (5 mL) and CH₃OH (5 mL) was added NaBH₄ (250 mg,6.5 mmol). After stirring at RT for 16 hr, the mixture was partitionedbetween DCM/CH₃OH (100 mL/5 mL) and brine (100 mL). The organic layerwas separated from aqueous layers, dried over Na₂SO₄ and concentrated toafford 250 mg (100%) of6-(hydroxymethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile,MS (ESI) m/e [M+1]⁺ 346.9.

Step 3:6-(Hydroxymethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared form6-(hydroxymethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrileusing the procedure similar to step 2 for compound 2. MS (ESI) m/e[M+1]⁺ 364.9.

Step 4:6-((1,3-Dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of isoindoline-1,3-dione (74 mg, 0.5 mmol) in THF (20 mL)was added PPh₃ (393 mg, 1.5 mmol) and6-(hydroxymethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide(180 mg, 0.5 mmol). DIAD (253 mg, 1.25 mmol) was added dropwise at 0° C.and stirred for 10 min. The mixture was allowed to warm to rt andstirred for 16 hr. Concentrated and purified by chromatography column on5 g of silica gel eluting with DCM/CH₃OH to afford 200 mg (62%) of6-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid. MS (ESI) m/e [M+1]⁺ 493.9.

Step 5:6-(Aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of6-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide(200 mg, 0.40 mmol) in CH₃OH (5 mL) was added hydrazine hydrate (1 mL,80% of aqueous solution). The mixture was stirred at 70° C. under N₂ for4 hr, concentrated and purified by chromatography column on 5 g ofsilica gel eluting with DCM/CH₃OH to afford 63 mg (43%) of6-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamideas colorless oil, MS (ESI) m/e [M+1]⁺ 363.9.

Step 6:6-(Actylamidomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared form6-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamideand acryloyl chloride using the procedure similar to that for compound8. ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (t, J=5.6 Hz, 1H), 7.51 (d, J=8.8Hz. 2H), 7.46-7.38 (m, 2H). 7.17 (t, J=7.6 Hz, 1H), 7.08 (d, J=7.6 Hz,2H). 7.04 (d, J=8.8 Hz, 2H), 6.61 (s, 1H), 6.25 (dd, J=17.1, 10.1 Hz,1H), 6.11 (dd, J=17.1,23 Hz, 1H), 5.62 (dd, J=10,1, 2.2 Hz, 1H). 4.07(dd, J=12.4, 6.0 Hz, 1H). 3.73 (dd, J=12,4, 8.0 Hz, 1H), 3.41-3.34 (m,1H), 3.27-3.21 (m. 2H), 3.09-2.96 (m. 1H), 2,37-2.24 (m, 1H). MS (ESI)m/e [M+1]⁺ 417.9.

Example 32 Synthesis of Compounds 87-88 Compound 87:2′-(4-Phenoxyphenyl)-5′,7′-dihydro-4′H-spiro[azetidine-3,6′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide

Step 1: Diethyl 1-benzylazetidine-3,3-dicarboxylate

To a solution of diethyl 2,2-bis(hydroxymethyl)malonate (4.4 g, 20 mmol)in CH₃CN (50 mL) was added Tf₂O (7.1 mL, 11.85 g, 42 mmol) at −20° C.followed by two batches of DIEA (6.45 g, 50 mmol). After 0.5 hr,benzylamine (3.21 g, 35 mmol) was added at −20° C. The mixture wasstirred at 70° C. for 2 hr. 100 mL of EA and 100 mL of brine were added.Organic layers were dried over Na₂SO₄. Purified by chromatography columnon silica get eluting with PE/EA to afford 4.8 g (82%) of diethyl1-benzylazetidine-3,3-dicarboxylate as a yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ 7.29-7.34 (m, 2H), 7.22-7.27 (m, 3H), 4.17 (q, J=7.2 Hz, 4H),3.56 (s, 2H), 3.51 (s, 4H), 2.39 (s, 3H) and 1.17 (t, J=7.2 Hz, 6H).

Step 2: (1-Benzylazetidine-3,3-diyl)dimethanol

To a solution of diethyl 1-benzylazetidine-3,3-dicarboxylate (4.8 g,16.5 mmol) in CH₃OH (10 mL) was added NaBH₄ (1.25 g, 33 mmol). Themixture was stirred at RT for 1 hr. 100 mL of brine and 200 mL of DOMwere added. Organic layers were separated from aqueous layers, driedover Na₂SO₄, concentrated to afford 2.328 g (68%) of(1-benzylazetidine-3,3-diyl)dimethanol as a yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ 7.21-7.31 (m, 5 H), 4.15-4.05, (m, 2H), 3.48 (d,J 4.8 Hz,2H), 3.17 (d, J=4.8 Hz, 4 H) and 2.89 (s, 2 H).

Step 3: (1-Benzylazetidine-3,3-diyl)bis(methylene)dimethanesulfonate

To a solution of (1-benzylazetidine-3,3-diyl)dimethanol (50 mg, 0.24mmol) in DCM (10 mL) was added TEA (222 mg, 2.2 mmoL) and MsCl (249 mg,2.2 mmol). After stirring for at RT for 4 hr, the mixture wasconcentrated. The residue was partitioned between brine (100 mL) and EA(100 mL). The organic layer was washed with brine (100 mL×2), dried overNa₂SO₄ and concentrated to afford 300 mg (83%) of crude(1-benzylazetidine-3,3-diyl)bis(methylene)dimethanesulfonate as a yellowoil. MS (ESI) m/e [M+1]⁺ 363.9.

Step 4:1-Benzyl-2′-(4-phenoxyphenyl)-5′,7′-dihydro-4′H-spiro[azetidine-3,6′-pyrazolo[1,5-a]pyrimidine]-3′-carbonitrile

To a solution of(1-benzylazetidine-3,3-diyl)bis(methylene)dimethanesulfonate (300 mg,0.83 mmol) in DMF (10 mL) was added5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile(230 mg, 0.83mmol) and K₂CO₃(230 mg, 1.66 mmol). The mixture was stirred at 80° C.under N₂ for 16 hr. The mixture was concentrated. The residue was washedwith H₂O (100 mL×2). dried and purified by pre-TLC (DCM/CH₃OH=10/1) toafford 30 mg (10%) of desired product as a yellow liquid, MS (ESI) m/e[M+1]⁺ 447.9.

Step 5:1-Benzyl-2′-(4-phenoxyphenyl)-5′,7′-dihydro-4′H-spiro[azetidine-3,6′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide

The desired product was prepared from1-benzyl-2′-(4-phenoxyphenyl)-5′,7′-dihydro-4′H-spiro[azetidine-3,6′-pyrazolo[1,5-a]pyrimidine]-3′-carbonitrileusing the procedure similar to step 2 for compound 2. MS (ESI) m/e[M+1]⁺ 465.9.

Step 6:2′-(4-Phenoxyphenyl)-5′,7′-dihydro-4′H-spiro[azetidine-3,6′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide

To a solution of1-benzyl-2′-(4-phenoxyphenyl)-5′,7′-dihydro-4′H-spiro[azetidine-3,6′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide(200mg, 0.43 mmol) in 10 mL of DCM and 10 mL of CH₃OH was added 10% w/w Pd/C(100 mg). After stirring at RT under H₂ for 16 hr. the mixture wasfiltered and concentrated. The residue was purified by pre-HPLC elutingfrom 25% to 90% CH3CN in 0.1% TFA in H₂O. Fractions containing thedesired product were combined and lyophilized overnight to afford 30 mg(19%) of desired product as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ8.94 (br s, 1H), 8.84 (br s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.46-7.38 (m,2H), 7.18 (t, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.4 Hz,2H), 6.81 (br s, 1H), 4.23 (s, 2H), 3.90-4.00 (m, 2H), 3.78-3.87 (m, 2H)and 3.47 (s, 2H). MS (ESI) m/e [M+1]⁺ 375.9.

Compound 88:1-Acryloyl-2′-(4-phenoxyphenyl)-5′,7′-dihydro-4′H-spiro[azetidine-3,6-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide

The desired product was prepared from compound 87 and acryloyl chlorideusing the procedure similar to that for compound 8. ¹H NMR (400 MHz,CD₃OD-d₄) δ 7.49 (d, J=7.6 Hz, 2H), 7.41-7.32 (m, 2H), 7.14 (t, J=8.0Hz, 1H), 7.05 (d, J=8.0 Hz, 2H), 7.04 (d, J=7.6 Hz, 2H), 6.35 (dd,J=16.8, 10.1 Hz, 1H), 6.25 (dd, J=16.8, 1.6 Hz, 1H), 5.74 (dd, J=10.1,1.6 Hz, 1H), 4.20-4.27 (m, 4H), 3.92-3.98 (m, 2H) and 3.54 (s, 2H). MS(ESI) m/e [M+1]⁺ 429.9.

Example 33 Synthesis of Compounds 89-90 Compound 89:6-(2-Aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydrapyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1:6-Bromo-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (28mg, 0.1 mmol), 2-bromomalonaldehyde (15 mg, 0.1 mmol) in EtOH (5 mL) wasstirred at RT for 2 hr. Then, the mixture was filtered to give the crudeproduct (20 mg, 62.9%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ9.89 (d, J=2.0 Hz, 1H), 8.95 (d, J=2.0 Hz, 1H), 8.08 (d, J=8.4 Hz, 2H),7.52-7.43 (m, 2H), 7.27-7.19 (m, 3H), 7.15 (d, J=7.6 Hz, 2H). MS (ESI,m/e) [M+1]⁺ 391.9.

Step 2:6-(2-Aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

A mixture of6-bromo-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (500mg, 1.28 mmol), 2-aminophenylboronic acid (175 mg, 1.28 mmol), Cs₂CO₃(623 mg, 1.92 mmol) and Pd(PPh₃)₄ (74 mg, 0.06 mmol) in 1,4-dioxane (30mL) and water (1.0 mL) was heated to 80° C. for 16 hr under N₂. Themixture was filtered and the filtrate was concentrated and purified bychromatography column on silica gel using 50% of EA in PE as eluant togive the crude product (320 mg, 59.1%) as a yellow solid, MS (ESI, m/e)[M+1]⁺ 403.9.

Step 3:6-(2-Aminophenyl)-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of6-(2-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile(320mg, 0.79 mmol) in MeOH (20 mL) was added NaBH₄ (86 mg, 2.28 mmol). Thesolution was stirred at rt for 30 min then was poured into water (50 mL)and extracted with EA (50 mL×3). The organic combined layers were driedover Na₂SO₄ and concentrated to give the crude product (240 mg, 75%) asa yellow solid. MS (ESI, m/e) [M+1]⁺ 406.0.

Step 4:6-(2-Aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbanitrile

The desired product was prepared from6-(2-aminophenyl)-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrileusing the procedure similar to step 8 for compound 68. MS (ESI, m/e)[M+1]⁺ 407.9.

Step 5:6-(2-Aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from6-(2-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrileusing the procedure similar to step 2 for compound 2. ¹H NMR (400 MHz,DMSO-d₆) δ 7.58 (d, J=8.4 Hz, 2H), 7.53-7.44 (m, 2H), 7.24 (t, J=7.6 Hz,1H), 7.19-7.09 (m, 4H), 7.06-7.99 (m, 2H), 6.84 (d, J=1.6 Hz, 1H), 6.74(d, J=7.2 Hz, 1H), 6.61 (t, J=7.6 Hz, 1H), 5.20 (s, 2H), 4.24 (dd,J=4.0, 12.0, Hz, 1H), 4.07 (dd, J=12.0, 12.0 Hz, 1H), 3.56-3.41 (m, 3H).MS (ESI, m/e) [M+1]⁺ 425.9.

Compound 90:6(3-Aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from6-bromo-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile and3-aminophenylboronic acid according to the similar procedures (step 2 to5) for compound 89 under appropriate conditions recognized by one ofordinary skill in the art. 1H NMR (400 MHz, DMSO-d₆) δ 7.59 (d, J=8.4Hz, 2H), 7.52-7.45 (m, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.15 (d, J=8.4 Hz,2H), 7.12 (d, J=7.6 Hz, 2H), 7.07 (t, J=7.6 Hz, 1H), 6.85 (br s, 1H),6.62-6.54 (m, 3H), 5.23 (br s, 2H), 4.24 (dd, J=12.0,4.8 Hz, 1H), 4.09(t, J=12.0 Hz, 1H), 3.56-3.50 (m, 1H), 3.40-3.35 (m, 1H), 3.28-3.19 (m,1H). MS (ESI, m/e) [M+1]⁺ 425.9.

Example 34 Synthesis of Compound 91 Compound 91:6-(3-(2-(Dimethylamino)ethoxy)phenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1:6-(3-Hydroxyphenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

To a solution of6-bromo-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (782mg, 2.0 mmol) in dioxane (10 mL) and H₂O (10 mL) was added3-hydroxyphenylboronic acid (276 mg, 2.0 mmol), Pd(PPh₃)₄ (240 mg, 0.2mmol) and Na₂CO₃ (424 mg, 4.0 mmol). After stirring at 65° C. under N₂for 16 hr, the mixture was concentrated and 100 mL of DCM, 10 mL ofCH₃OH, 100 mL of H₂O were added. Organic layers were separated fromaqueous layers and dried over Na₂SO₄ and purified by chromatographycolumn on silica gel eluting with DCM/CH₃OH to afford 500 mg (62%) of6-(3-hydroxyphenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. MS (ESI) m/e[M+1]⁺ 404.9.

Step 2:6-(3-Hydroxyphenyl)-2-(4-phenoxyphenyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrileand 6-(3-hydroxyphenyl)-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

The desired product was prepared from6-(3-hydroxyphenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrileusing the procedure similar to step 3 for compound 89. MS (ESI) m/e[M+1]⁺ 406.9.

Step 3:6-(3-Hydroxyphenyl)-2-(4-phenoxyphenyl)4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile

The desired product was prepared from intermediate in the last stepusing the procedure similar to step 4 for compound 89. MS (MSI) m/e[M+1]⁺ 408.9.

Step 4:6-(3-Hydroxyphenyl)-2-(4-phenoxyphenyl)-4,5,6,7-(tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from6-(3-hydroxyphenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrileusing the procedure similar to step 2 for compound 2. MS (ESI) m/e[M+1]⁺ 426.9.

Step 5:6-(3-(2-(Dimethylamino)ethoxy)phenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

The desired product was prepared from6-(3-hydroxyphenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamideand 2-chloro-N,N-dimethylethanamine hydrochloride using the proceduresimilar to step 7 for compound 9. ¹H NMR (400 MHz, DMSO-d6) δ 7.52 (d,J=8.4 Hz, 2H), 7.46-7.38 (m, 2H), 7.29 (t,J =7.6 Hz, 1H), 7.18 (t, J=7.6Hz, 1H), 7.10-7.05 (m, 4H), 6.98-6.96 (m, 2H), 6.90-6.88 (m, 1H), 6.81(d, J=2.4 Hz, 1H), 4.25-4.20 (m, 1H), 4.16-4.11 (m, 3H), 3.50-3.47 (m,1H), 3.43-3.38 (m, 2H), 2.96-2.84 (m, 2H) and 2.43 (s, 6H), MS (ESI) m/e[M+1]⁺ 497.9.

Compound 178:N1-(2-(4-((E)-4-(4-((S)-3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)-N5-(15-oxo-19-((3aR,4R,6aS)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)glutarumidetrifluoroacetate

The desired compound was prepared according to the scheme, step andintermediates described below.

Step 1:(E)-4-(4-(2-((tert-butoxycarbonyl)amino)ethyl)piperazin-1-yl)but-2-enoicacid

A mixture of (E)-4-bromobut-2-enoic acid (500 mg, 3.03 mmol), tert-butyl(2-(piperazin-1-yl)ethyl)carbamate (694 mg, 3.03 mmol) and Et₃N (612 mg,6.06 mmol) in 20 mL of THF was stirred at RT for 15 h. The mixture wasconcentrated and used in the next step without further purification. MS(ESI) m/e [M+1]⁺ 314.0.

Step 2:(S)-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (2.0 g, 4.8 mmol) in MeOH/H₂O=3/1 (110mL) was warmed to 50° C. and stirred for about 20 min until all startingmaterial dissolved, then to solution was added a solution of L-DBTA (600mg, 1.6 mmol), in MeOH/H₂O=3/1 (10 mL). the solution was stirred at 50°C. for about 30 min, then slowly cooled to 40° C. (about 2 h). To thesolution was added crystal seed (10 mg). The mixture was stirred at 40°C. for 2 h, then slowly cooled to ambient temperature and stirred forabout 48 h. Filtered, the solid was washed with MeOH/H₂O=3/1 (5 mL),dried under reduced pressure to give the product as a white solid about1.1 g (38% yield, 93% ee value). The solid (500 mg) was added to thesolvent of THF/H₂O=1/1 (20 mL), the solution was warmed to 70° C. andstirred for about 1 h until all solid dissolved, then slowly cooled to40° C. (3 h) and added crystal seed (10 mg), after stirring for about 2h, the solution was slowly cooled to ambient temperature and stirred forabout 48 h. Filtered, solid was washed with water (4 mL), dried underreduced pressure to give the product as a white solid about 330 mg (65%yield, >99.5% ee value) as its L-DBTA salt. Suitable single crystal ofthis L-DBTA salt was obtained by slow cooling in MeOH/H₂O (1:1, v/v).Configuration of chiral carbon in freebase was determined to be S. TheDBTA salt was converted to the free base by using aqueous NaOH solutionand extracting with DCM.

The chiral analysis conditions for the chiral resolution are shownbelow.

Column CHIRALPAK IC Column size 0.46 cm I.D. × 15 cm L, 5 um Injection 2uL Mobile phase n-Hexane/EtOH(0.1% triethylamine) = 50/50 (v/v) Flowrate 1.0 mL/min Wave length UV 214, 254 nm

Step 3: (S,E)-tert-butyl(2-(4-(4-(4-(3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)carbamate

A mixture of(S)-2-(4-phenoxypheny)-7-(piperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide(1.26 g, 3.03 mmol), (E)-4-(4-(2-((tert-butoxycarbonyl)amino)ethyl)piperazin-1-yl)but-2-enoic acid (948.4 mg, 3.03 mmol), HATU(1.21 g, 3.18 mmol), DIEA (782 mg, 6.06 mmol) in 30 mL of DMF wasstirred at RT for 15 hr. The mixture was poured into 300 mL of water andextracted with HA (100 mL). The organic phase was washed with water (100mL×3) and concentrated to give 1.25 g (58%) of product as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (d, J=8.4 Hz, 2H), 7.42 (t,J=8.4 Hz, 2H), 7.17 (t, J=7.4 Hz, 1H), 7.12-7.02 (m, 4H), 6.67 (br s,1H), 6.64-6.53 (m, 3H), 4.53-4.40 (m, 1H), 4.14-4.05 (m, 1H), 3.32-3.25(m, 2H), 3.10-2.91 (m, 5H), 2.45-2.15 (m, 11H), 2.10-2.00 (m, 1H),1.96-1.84 (m, 1H), 1.78-1.65 (m, 1H), 1.62-1.50 (m, 1H), 1.37 (s, 9H),1.31-1.10 (m, 3H). MS (ESI) m/e [M+1]⁺ 713.0.

Step 4:(S,E)-7-(1-(4-(4-(2-aminoethyl)piperazin-1-yl)but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate

To a solution of (S,E)-tertbutyl(2-(4-(4-(4-(3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)carbamate (150 mg, 0.21 mmol) in 10 mL of DCM was added 2 mL ofTFA. The reaction mixture was stirred at RT for 15 hr and concentratedto remove the solvent. The residue was used in the next step withoutfurther purification. MS (ESI) m/e [M+1]⁺ 613.0.

Compound 178:N1-(2-(4-((E)-4-(4-((S)-3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)-N5-(15-oxo-19-((3aR,4R,6aS)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)glutaramidetrifluoroacetate

A mixture of(S,E)-7-(1-(4-(4-(2-aminoethyl)piperazin-1-yl)but-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenyl)4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamidetrifluoroacetate (129 mg, 0.21 mmol, crude),N-BIOTINYL-NH-(PEG)2-COOH-DIEA (118 mg, 0.21 mmol), HATU (80 mg, 0.21mmol). TEA (63.6 mg, 0.63 mmol) in 5 mL of DMF was stirred at 40° C. for15 hr. The mixture was concentrated and purified by Pre-HPLC to afford160 mg (60%) of product as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.04 (t, J=5.2 Hz, 1H), 7.80 (t, J=5.6 Hz, 1H), 7.76 (t, J=5.6 Hz, 1H),7.50 (d, J=8.5 Hz, 2H), 7.42 (t, J=8.5 Hz, 2H), 7.18 (t, J=7.6 Hz, 1H),7.12-7.03 (m, 4H), 6.89-6.77 (m, 1H), 6.62-6.51 (m, 1H), 6.44 (s, 1H),4.55-4.40 (m, 1H), 4.35-4.27 (m, 1H), 4.17-3.95 (m, 3H), 3.74-3.60 (m,2H), 3.55-3.44 (m, 9H), 3.41-3.27 (m, 10H), 3.14-3.02 (m, 9H), 2.82 (dd,J=12.4, 5.0 Hz, 1H). 2.65-2.53 (m, 3H), 2.36-2.18 (m, 1H), 2.13-2.00 (m,7H), 1.96-1.85 (m, 1H), 1.80-1.67 (m, 3H), 1.66-1.55 (m, 6H), 1.55-1.40(m, 3H), 1.38-1.21 (m, 4H). MS (ESI) m/e [M+1]⁺ 1155.0, [M+23]⁺ 1176.9.

Compound 181:(S)-7-(1-(2-cyano-3-cyclopropylacryloyl)piperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of compound 180 (60 mg, 0.124 mmol), cyclopropanecarbaldehyde(43.4 mg, 0.62 mmol) and piperdine (52.7 mg, 0.62 mmol) in MeOH (10 mL)was stirred at RT for 15 h. After concentration, to the residue wasadded EA (50 mL) and water (50 mL). The organic phase was concentratedand purified by chromatography column on silica gel eluting withDCM/MeOH (50/1) to afford 30 mg (45%) of desired compound as a whitesolid. MS (ESI) m/e [M+1]⁺ 537.0.

Compound 182:(S)-7-(1-cyanopiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of(S)-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide(417 mg, 1 mmol) In DGM (20 mL) was added NaHCO₃ (168 mg, 2 mmol) andwater (5 mL), followed by BrCN (127 mg, 1.2 mmol). The mixture wasstirred at RT for 16 h. To the mixture was added DCM (50 mL) and brine(20 mL). The organic phase was further washed with brine (100 mL), driedover Na₂SO₄. Concentrated and purified by Pre-TLC (DCM/MeOH, 50/1) toafford 330 mg (75%) of white solid. MS (SSI) m/e [M+1]⁺ 443.0.

A variety of other compounds have been prepared by methods substantiallysimilar to those of above described Examples. The characterization datafor some of these compounds are summarized in Table 1 below and includeLC/MS (observed), chiral HPLC and ¹H NMR data.

TABLE 1 Characterization Data for Selected Compounds ¹H NMR data, ChiralHPLC and LC/MS No. Name m/z (M + 1) Structure  92 (E)-7-(2-(4-(dimethylamino) but-2- enamido)phenyl)- 2-(4- phenoxyphenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ9.74 (s, 1H), 7.52- 7.44 (m, 3H), 7.44-7.36 (m, 2H), 7.29 (t, J = 7.6Hz, 1H), 7.21-7.04 (m, 2H), 7.11- 6.97 (m, 4H), 6.88-6.67 (m, 2H), 6.64(d, J = 7.6 Hz, 1H, (6.37 (d, J = 15.1 Hz, 1H), 5.81-5.74 (m, 1H),3.32-3.22 (m, 1H), 3.07 (d, J = 5.6 Hz, 2H), 3.03-2.93 (m, 1H),2.38-2.26 (m, 1H), 2.19 (s, 6H), 2.05-1.95 (m, 1H). MS (ESI) m/e [M +1]⁺ 536.9.

 93 7-(2- Aminophenyl)- 2-(4-methoxy- phenyl)-4,5,6,7- tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ 7.40 (d, J= 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.75(s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.49 (t, J = 7.6 Hz, 1H), 6.27 (d, J= 7.6 Hz, 1H), 5.57 (s, 1H), 5.16 (s, 2H), 3.78 (s, 3H), 3.28-3.21 (m,1H), 2.99-2.91 (m, 1H), 2.26-2.04 (m, 2H). MS (ESI) m/e [M + 1]⁺ 363.9.

 94 7-(2- acrylamidophenyl)- 2-(4-methoxy- phenyl)-4,5,6,7- tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ 9.84 (s,1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40 (, J = 8.8 Hz, 2H), 7.30 (t, J = 7.6Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.82 (s,1H), 6.64 (d, J = 8.0 Hz, 1H), 6.53 (dd, J = 17.0, 10.2 Hz, 1H), 6.27(dd, J = 17.0, 1.8 Hz, 1H), 5.82-5.74 (m, 2H), 3.77 (s, 3H), 3.31-3.19(m, 1H), 3.03-2.91 (m, 1H), 2.38-2.24 (m, 1H), 2.02-1.92 (m, 1H). MS(ESI) m/e [M + 1]⁺ 417.9.

 95 7-(5-amino-2- chlorophenyl)-2- (4-phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(CD₃OD-d₄) δ 7.52-7.44 (m, 2H), 7.40-7.31 (m, 2H), 7.19-7.06 (m, 2H),7.06- 6.98 (m, 4H), 6.58 (dd, J = 8.4, 2.6 Hz, 1H), 6.10 (d, J = 2.6 Hz,1H), 5.71 (dd, J = 2.0, 5.2 Hz, 1H), 3.367 (dt, J = 12.4, 3.6 Hz, 1H),3.21 (t, J = 12.4, 3.6 Hz, 1H), 2.50-2.40 (m, 1H), 2.30-2.23 (m, 1H). MS(ESI) m/e [M + 1]⁺ 460.1.

 96 7-(5- acrylamido-2- chlorophenyl)-2- (4-phenoxy- phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ10.32 (s, 1H), 8.14 (s, 1H), 7.88 (dd, J = 8.4, 2.0 Hz, 1H), 7.51-7.46(m, 3H), 7.40 (t, 2H, J = 7.6, 7.6 Hz), 7.16 (t, J = 7.6 Hz, 1H),7.07-7.01 (m, 5H), 6.95 (br s, 1H), 6.37 (dd, J = 17.0, 10.0 Hz, 1H),6.23 (dd, J = 17.0, 1.4 Hz, 1H), 5.74 (dd, J = 10.0, 1.4 Hz, 1H), 5.68-5.64 (m, 1H), 3.12-3.02 (m, 1H), 2.46-2.39 (m, 2H), 2.10-2.05 (m, 1H).MS (ESI) m/e [M + 1]⁺ 513.9.

 97 7-(3- acrylamido-4- chlorophenyl)-2- (4-phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(DMSO-d₆) δ 9.77 (s, 1H), 7.57 (s, 1H), 7.53-7.46 (m, 3H), 7.44-7.35 (m,2H), 7.16 (t, J = 7.6 Hz, 1H), 7.08-7.00 (m, 4H), 6.91 (d, J = 7.6 Hz,1H), 6.83 (br s, 1H), 6.59 (dd, J = 17.1, 10.0 Hz, 1H), 6.27 (d, J =17.1 Hz, 1H), 5.78 (d, J = 10.0 Hz, 1H), 5.50-5.45 (m, 1H), 3.33 (m,1H), 3.13- 3.03 (m, 1H), 2.42-2.31 (m, 1H), 2.14-2.04 (m, 1H). MS (ESI)m/e [M + 1]⁺ 513.9.

 98 7-(4- aminophenyl)-2- (4-phenoxyphenyl)- 4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d6) δ 7.50 (d, J= 8.4 Hz, 2H), 7.41-7.32 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.03-6.98(m, 4H), 6.69-6.67 (m, 3H), 6.48 (d, J = 8.4 Hz, 2H), 5.24-5.19 (m, 1H),4.99 (s, 2H), 3.26-3.22 (m, 1H), 3.07-3.00 (m, 1H), 2.28-2.20 (m, 1H),2.00-1.95 (m, 1H). MS (ESI) m/e [M + 1]⁺ 426.0.

 99 7-(4-Acrylamido- phenyl)-2-(4- phenoxyphenyl)- 4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamie ¹H NMR (DMSO-d₆) δ 10.14 (s,1H), 7.60 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.40-7.32 (m,2H), 7.12 (t, J = 7.6 Hz, 1H), 6.94-7.06 (m, 6H), 6.75 (s, 1H), 6.39(dd, J = 10.1, 17.0 Hz, 1H), 6.21 (dd, J = 1.8, 17.0 Hz, 1H), 5.71 (dd,J = 1.8, 10.1 Hz, 1H), 5.41-5.36 (m, 1H), 3.27-3.22 (m, 1H), 3.07-2.97(m, 1H), 2.37-2.24 (m, 1H), 2.08-1.95 (m, 1H). MS (ESI) m/e [M + 1]⁺480.

100 2-(4- phenoxyphenyl)- 7-(pyridin-4-yl)- 4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ 8.57 (d, J= 6.0 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.45-7.37 (m, 2H), 7.22-7.10(m, 3H), 7.07-7.03 (m, 4H), 6.86-6.83 (m, 1H), 5.56-5.10 (m, 1H), 3.35-3.29 (m, 1H), 3.00-2.94 (m, 1H), 2.48-2.38 (m, 1H), 2.18-2.14 (m, 1H).MS (ESI) m/e [M + 1]⁺ 412.2.

101 2-(4- phenoxyphenyl)- 7-(pyridin-3-yl)- 4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ 8.51 (dd, J= 1.6, 4.8 Hz, 1H), 8.37 (d, J = 1.6 Hz, 1H), 7.52- 7.44 (m, 3H),7.42-7.38 (m, 3H), 7.19-7.13 (m, 1H), 7.07-7.02 (m, 4H), 6.84 (br s,1H), 5.56-5.51 (m, 1H), 3.34-3.30 (m, 1H), 3.13- 3.03 (m, 1H), 2.46-2.40(m, 1H), 2.21-2.14 (m, 1H). MS (ESI) m/e [M + 1]⁺ 411.9.

102 2-(4- phenoxyphenyl)- 7-(pyridin-2-yl)- 4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ 8.57 (d, J= 4.4 Hz, 1H), 7.79 (td, J = 1.6, 7.6 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H),7.40 (t, J = 8.0 Hz, 2H), 7.36-7.28 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H),7.09-7.00 (m, 5H), 6.81 (br s, 1H), 5.48- 5.43 (m, 1H), 3.31-3.25 (m,1H), 3.10-3.02 (m, 1H), 2.42-2.28 (m, 2H). MS (ESI) m/e [M + 1]⁺ 411.9.

103 7-(1- acryloylpyrrolidin- 2-yl)-2-(4- phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(DMSO-d₆) δ 7.49 (d, J = 8.6 Hz, 2H), 7.46-7.38 (m, 2H), 7.20-7.15 (m,1H), 7.09 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.76 (s, 1H),6.62 (dd, J = 16.8, 10.3 Hz, 1H), 6.16 (dd, J = 16.8, 2.2 Hz, 1H), 5.70(dd, J = 10.3, 2.2 Hz, 1H), 4.47- 4.40 (m, 1H), 4.36-4.28 (m, 1H),3.65-3.50 (m, 2H), 3.50-3.40 (m, 1H), 3.37-3.33 (m, 1H), 2.06-1.74 (m,6H). MS (ESI) m/e [M + 1]⁺ 457.9.

104 7-(1- acryloylazetidin- 3-yl)-2-(4- (benzyloxy)phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(DMSO-d₆) δ 7.49-7.45 (m, 2H), , 7.44-7.37 (m, 4H), 7.37-7.31 (m, 1H),7.10- 7.07 (m, 2H), 6.68 (s, 1H), 6.38-6.25 (m, 1H), 6.12-6.04 (m, 1H),5.69-5.57 (m, 1H), 5.17-5.12 (m, 2H), 4.42-3.78 (m, 5H), 3.31- 3.25 (m,2H), 3.04-2.88 (m, 1H), 2.15-2.04 (m, 1H), 1.79-1.68 (m, 1H). MS (ESI)m/e [M + 1]⁺ 457.9.

105 7-(1-acryloyl- azetidin-3-yl)-2- (4-(pyridin-2- ylmethoxy)phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(400 MHz, dmso) δ 8.61-8.57 (m, 1H), 7.90-7.78 (m, 1H), 7.56-7.52 (m,1H), 7.44-7.39 (m, 2H), 7.38-7.34 (m, 1H), 7.12- 7.08 (m, 2H), 6.68 (s,1H), 6.39-6.23 (m, 1H), 6.12-6.01 (m, 1H), 5.68-5.59 (m, 1H), 5.24-5.21(m, 2H), 4.44-4.23 (m, 2.5H), 4.19-4.07 (m, 1H), 4.04-3.94 (m, 1H),3.88- 3.78 (m, 0.5H), 3.31-3.24 (m, 2H), 3.02- 2.88 (m, 1H), 2.15-2.03(m, 1H), 1.80-1.68 (m, 1H). MS (ESI) m/e [M + 1]⁺ 458.9

106 7-(1-acryloyl- azetidin-3-yl)-2- (4-(4-chloro- phenoxy)phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(DMSO-d₆) δ 7.52 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.11 (d,J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.69 (s, 1H), 6.38-6.22 (m,1H), 6.13-6.03 (m, 1H), 5.70-5.60 (m, 1H), 4.43-4.26 (m, 2.5H),4.19-4.08 (m, 1H), 4.05-3.95 (m, 1H), 3.87-3.79 (m, 0.5H), 3.31-3.25 (m,2H), 3.04-2.90 (m, 1H), 2.15-2.05 (m, 1H), 1.80-1.66 (m, 1H). MS (ESI)m/e [M + 1]⁺ 477.9.

107 7-(1-acryloyl- azetidin-3-yl)-2- (4-(3-chloro- phenoxy)phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(DMSO-d₆) δ 7.54 (d, J = 8.4 Hz, 2H), 7.46-7.40 (m, 1H), 7.25-7.19 (m,1H), 7.18-7.15 (m, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.07-7.02 (m, 1H),6.69 (s, 1H), 6.39-6.26 (m, 1H), 6.13-6.01 (m, 1H), 5.69-5.60 (m, 1H),4.45-4.24 (m, 2.5H), 4.19-4.09 (m, 1H), 4.06-3.94 (m, 1H), 3.88-3.80 (m,0.5H), 3.32-3.24 (m, 2H), 3.05-2.90 (m, 1H), 2.15-2.04 (m, 1H),1.80-1.68 (m, 1H). MS (ESI) m/e [M + 1]⁺ 477.9.

108 7-(1-acrylamido- cyclopropyl)-2-(4- phenoxyphenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ8.41 (s, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.46-7.38 (m, 2H), 7.21-7.15 (m,1H), 7.11-7.04 (m, 4H), 6.75 (s, 1H), 6.21 (dd, J = 17.1, 9.9 Hz, 1H),6.09 (dd, J = 17.1, 2.4 Hz, 1H), 5.58 (dd, J = 9.9, 2.4 Hz, 1H),4.36-4.30 (m, 1H), 3.44-3.35 (m, 2H), 2.31-2.19 (m, 1H), 1.96- 1.82 (m,1H), 1.08-1.00 (m, 1H), 0.81-0.73 (m, 1H), 0.72-0.59 (m, 2H). MS (ESI)m/e [M + 1]⁺ 443.9.

109 7-(2-acrylamido- propan-2-yl)-2- (4-phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(DMSO-d₆) δ 8.06 (s, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.46-7.37 (m, 2H),7.17 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.6 Hz,2H), 6.77 (s, 1H), 6.28 (dd, J = 17.1, 10.1 Hz, 1H), 6.06 (dd, J = 17.1,1.6 Hz, 1H), 5.56 (dd, J = 10.1, 1.6, Hz, 1H), 4.80 (t, J = 5.4 Hz, 1H),3.32-3.26 (m, 2H), 2.11-1.82 (m, 2H). MS (ESI) m/e [M + 1]⁺ 445.9.

110 7-(aminomethyl)- 2-(4- (benzyloxy)phenyl)- 4,5,6,7- tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide trifluoroacetate ¹H NMR(DMSO-d₆) δ 7.97 (s, 3H), 7.50- 7.44 (m, 4H), 7.43-7.38 (m, 2H),7.37-7.31 (m, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.80 (s, 1H), 5.15 (s, 2H),4.43-4.29 (m, 1H), 3.35- 3.21 (m, 4H), 2.20-2.09 (m, 1H), 2.04-1.91 (m,1H). MS (ESI) m/e [M + 1]⁺ 337.9.

111 7-(acrylamido- methyl)-2-(4- (benzyloxy)phenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ8.29 (t, J = 6.1 Hz, 1H), 7.51-7.31 (m, 6H), 7.10 (d, J = 8.8 Hz, 1H),6.68 (s, 1H), 6.26 (dd, J = 17.1, 10.1, Hz, 1H), 6.11 (dd, J = 17.1, 2.1Hz, 1H), 5.62 (dd, J = 10.1, 2.1 Hz, 1H), 5.15 (s, 2H), 4.21-4.12 (m,1H), 3.84-3.68 (m, 1H), 3.45-3.36 (m, 1H), 3.32-3.23 (m, 2H), 2.10- 1.85(m, 2H). MS (ESI) m/e [M + 1]⁺ 431.9.

112 7-(aminomethyl)- 2-(4- (cyclopropyl- methoxy)phenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ7.39 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.63 (s, 1H),4.06-3.94 (m, 1H), 3.85 (d, J = 7.0 Hz, 2H), 3.04 (dd, J = 12.8, 6.8 Hz,1H), 2.87 (dd, J = 12.8, 6.8 Hz, 1H), 2.12-1.91 (m, 2H), 1.30-1.18 (m,2H), 0.62-0.50 (m, 2H), 0.36- 0.28 (m, 2H). MS (ESI) m/e [M + 1]⁺ 342.0.

113 7-(acrylamido- methyl)-2-(4- (cyclopropyl- methoxy)phenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (CD₃OD-d₄)δ 7.43 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.32-6.18 (m, 2H),5.70-5.65 (m, 1H), 4.32-4.22 (m, 1H), 3.87 (d, J = 6.9 Hz, 2H),3.80-3.66 (m, 2H), 3.52-3.36 (m, 2H), 2.22-1.96 (m, 2H), 1.34- 1.20 (m,1H), 0.66-0.57 (m, 2H), 0.39-0.30 (m, 2H). MS (ESI) m/e [M + 1]⁺ 395.9.

114 Cis-7-(1-tert- Butoxycarbonyl)- 2-(4- phenoxyphenyl)- 5,5a,6,7,8,8a-hexahydro-4H- pyrazolo[1,5- a]pyrrolo[3,4- e]pyrimidine-3- carboxamide¹H NMR (DMSO-d₆) δ 7.52 (d, J = 7.6 Hz, 2H), 7.46-7.38 (m, 2H), 7.18 (t,J = 7.6 Hz, 1H), 7.11-7.03 (m, 4H), 6.71 (br s, 1H), 4.61-4.54 (m, 1H),3.87 (t, J = 11.6 Hz, 1H), 3.67-3.48 (m, 2H), 3.30-3.12 (m, 3H),3.06-2.85 (m, 1H), 1.36 (d, 9H). MS (ESI) m/e [M + 1]⁺ 476.0.

115 Cis-2-(4- phenoxyphenyl)- 5,5a, 6,7,8,8a- hexahydro-4H-pyrazolo[1,5- a]pyrrolo[3,4- e]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆and D₂O) δ 7.53 (d, J = 8.8 Hz, 2H), 7.44-7.40 (m, 2H), 7.23- 7.16 (m,1H), 7.13-7.04 (m, 4H), 4.79-4.73 (m, 1H), 3.78 (d, J = 12.8 Hz, 1H),3.57- 3.27 (m, 4H), 3.14-3.03 (m, 2H). MS (ESI) m/e [M + 1]⁺ 376.0.

116 Cis-7-acryloyl- 2-(4- phenoxyphenyl)- 5,5a,6,7,8,8a- hexahydro-4H-pyrazolo[1,5- a]pyrrolo[3,4- e]pyrimidine-3- carboxamide ¹H NMR(DMSO-d₆) δ 7.51 (dd, J = 2.0, 8.4 Hz, 2H), 7.45-7.38 (m, 2H), 7.18 (t,J = 7.6 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H),6.75 (s, 1H), 6.62-6.48 (m, 1H), 6.14-6.04 (m, 1H), 5.69-5.61 (m, 1H),4.70-4.61 (m, 1H), 4.20-4.10 (m, 1H), 3.98-3.86 (m, 1H), 3.72-3.67 (m,1H), 3.50- 3.40 (m, 1H), 3.42-3.38 (m, 1H), 3.33-3.28 (m, 1H), 3.13-2.94(m, 1H). MS (ESI) m/e [M + 1]⁺ 430.0

117 2-(1- acryloylpyrrolidin- 3-yl)-6-(4- phenoxyphenyl)- 1H-imidazo[1,2- b]pyrazole-7- carboxamide ¹H NMR (DMSO-d₆) δ 11.76 (s, 1H),7.67 (d, J = 8.0 Hz, 2H), 7.56 (s, 1H), 7.47-7.38 (m, 2H), 7.17 (t, J =7.6 Hz, 1H), 7.109 (d, J = 7.6 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.60(ddd, J = 2.2, 10.3, 16.6 Hz, 1H), 6.16 (dd, J = 2.2, 16.6 Hz, 1H), 5.69(dd, J = 2.2, 10.3 Hz, 1H), 4.09-3.95 (m, 1H), 3.94- 3.73 (m, 1H),3.70-3.37 (m, 3H), 2.42-2.24 (m, 1H), 2.21-2.01 (m, 1H). MS (ESI) m/e[M + 1]⁺ 441.9.

118 2′-(4- phenoxyphenyl)- 5′,6′-dihydro-4′H- spiro[azetidine- 3,7′-pyrazolo[1,5- a]pyrimidine]- 3′-carboxamie ¹H NMR (DMSO-d₆) δ 7.63 (d, J= 8.4 Hz, 2H), 7.55-7.47 (m, 2H), 7.21-7.14 (m, 4H), 6.88 (s, 1H), 4.47(d, J = 9.8 Hz, 2H), 3.81 (d, J = 9.8 Hz, 2H), 3.35-3.33 (m, 2H),2.51-2.44 (m, 2H). MS (ESI) m/e [M + 1]⁺ 375.9.

119 1-acryloyl- 2′-(4- phenoxyphenyl)- 5′,6′-dihydro-4′H-spiro[azetidine- 3,7′- pyrazolo[1,5- a]pyrimidine]- 3′-carboxamie ¹H NMR(DMSO-d₆) δ 7.54 (d, J = 8.6 Hz, 2H), 7.46-7.38 (m, 2H), 7.17 (t, J =7.6 Hz, 1H), 7.11-7.05 (m, 4H), 6.79 (s, 1H), 6.35 (dd, J = 17.0, 10.3Hz, 1H), 6.14 (dd, J = 17.0, 2.1 Hz, 1H), 5.70 (dd, J = 10.3, 2.1 Hz,1H), 4.66 (d, J = 8.8 Hz, 1H), 4.38 (d, J = 10.0 Hz, 1H), 4.32 (d, J =8.8 Hz, 1H), 4.03 (d, J = 10.0 Hz, 1H), 3.31-3.26 (m, 2H), 2.38-2.31 (m,2H). MS (ESI) m/e [M + 1]⁺ 429.9.

120 2-(4- phenoxyphenyl)- 4,5,6,7,8,9- hexahydro- pyrazolo[1′,5′:1,2]imidazo[4,5- d]azepine-3- carboxamide ¹H NMR (DMSO-d₆) δ 11.74 (br s,1H), 9.06 (br s, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.47-7.39 (m, 2H), 7.18(t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.6 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H),3.19-3.14 (m, 2H), 3.10-3.05 (m, 2H). MS (ESI) m/e [M + 1]⁺ 387.9.

121 7-acryloyl-2-(4- phenoxyphenyl)- 4,5,6,7,8,9- hexahydro-pyrazolo[1′,5′:1,2] imidazo[4,5- d]azepine-3- carboxamide ¹H NMR(CD₃OD-d₄) δ 7.64-7.60 (m, 2H), 7.43-7.37 (m, 2H), 7.19-7.14 (m, 1H),7.12- 7.05 (m, 4H), 6.97-6.85 (m, 1H), 6.32 (dd, J = 2.0, 16.8 Hz, 1H),5.81 (dd, J = 2.0, 8.4 Hz, 1H), 4.04-3.91 (m, 4H), 3.17-3.09 (m, 2H),3.07-3.01 (m, 2H). MS (ESI) m/e [M + 1]⁺ 441.9.

122 (E)-7-(4- (dimethylamino) but-2-enoyl)-2-(4- phenoxyphenyl)-4,5,6,7,8,9- hexahydro- pyrazolo[1′,5′:1,2] imidazo[4,5- d]azepine-3-carboxamide ¹H NMR (CD₃OD-d₄) δ 7.59 (d, J = 8.4 Hz, 2H), 7.41-7.32 (m,2H), 7.15 (t, J = 7.6 Hz, 1H), 7.10-6.99 (m, 5H), 6.80-6.70 (m, 1H),4.08-3.84 (m, 6H), 3.15-3.08 (m, 2H), 3.06- 3.01 (m, 2H), 2.90 (s, 3H),2.89 (s, 3H). MS (ESI) m/e [M + 1]⁺ 498.9.

123 8-acryloyl-2-(4- phenoxyphenyl)- 4,5,6,7,8,9- hexahydro-pyrazolo[5′,1′:2,3] imidazo[4,5- c]azepine-3- carboxamide As a byproductin the preparation of compound 121 ¹H NMR (CD₃OD-d₄) δ 7.61 (dd, J =2.4, 8.8 Hz, 2H), 7.41-7.33 (m, 2H), 7.14 (t, J = 8.0 Hz, 1H), 7.11-7.02(m, 4H), 6.82 (dd, J = 10.6, 16.8 Hz, 1H), 6.19 (dd, J = 1.8, 16.8 Hz,1H), 5.74 (dd, J = 1.8, 10.6 Hz, 1H), 4.98 (d, J = 12.4 Hz, 2H),4.06-3.80 (m, 2H), 2.96-2.89 (m, 2H), 2.12-1.93 (m, 2H). MS (ESI) m/e[M + 1]⁺ 441.9.

124 (E)-8-(4- (dimethylamino) but-2-enoyl)-2-(4- phenoxyphenyl)-4,5,6,7,8,9- hexahydro- pyrazolo[5′,1′:2,3] imidazo[4,5- c]azepine-3-carboxamide As a byproduct in the preparation of compound 122. ¹H NMR(CD₃OD-d₄) δ 7.54 (dd, J = 2.4, 8.8 Hz, 2H), 7.34-7.26 (m, 2H),7.10-7.04 (m, 1H), 7.03-6.95 (m, 4H), 6.75-6.50 (m, 2H), 4.90 (d, J =11.6 Hz, 2H), 3.89-3.77 (m, 2H), 3.17-3.12 (m, 2H), 2.88-2.82 (m, 2H),2.28 (s, 3H), 2.19 (s, 3H), 2.02-1.90 (m, 2H). MS (ESI) m/e [M + 1]⁺498.9.

125 2-(4- (benzyloxy)phenyl)- 5,6,7,8- tetrahydro-4H-pyrazolo[5′,1′:2,3] imidazo[4,5- c]pyridine-3- carboxamide formate ¹HNMR (DMSO-d₆) δ 11.94 (s, 1H), 9.78 (s, 1H), 9.33 (s, 2H), 7.30-7.22 (m,5H), 7.18-7.13 (m, 1H), 6.95-6.85 (m, 1H), 4.41 (s, 2H), 3.91 (s, 2H),2.94-2.87 (m, 2H). MS (ESI) m/e [M + 1]⁺ 387.9.

126 7-Acryloyl-2-(4- (benzyloxy)phenyl)- 5,6,7,8- tetrahydro-4H-pyrazolo[5′,1′:2,3] imidazo[4,5- c]pyridine-3- carboxamide ¹H NMR(DMSO-d₆) δ 9.70 (s, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.35-7.29 (m, 2H),7.28-7.23 (m, 1H), 7.19 (d, J = 8.2 Hz, 2H), 6.95-6.87 (m, 1H),6.86-6.83 (m, 2H), 6.20- 6.07 (m, 1H), 5.74-5.73 (m, 3H), 4.80-4.72 (m,2H), 3.89-3.87 (m, 2H), 2.69-2.67 (m, 2H). MS (ESI) m/e [M + 1]⁺ 441.9.

127 7-acryloyl-2-(4- (cyclopropyl- methoxy)phenyl)- 5,6,7,8-tetrahydro-4H- pyrazolo[5′,1′:2,3] imidazo[4,5- c]pyridine-3-carboxamide ¹H NMR (DMSO-d₆) δ 9.67 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H),7.01-6.89 (m, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.22-6.11 (m, 1H),5.80-5.70 (m, 1H), 4.85-4.70 (m, 2H), 4.30- 4.26 (m, 2H), 3.99-3.90 (m,2H), 2.90-2.80 (m, 2H), 1.18-1.06 (m, 1H), 0.44-0.30 (m, 4H). MS (ESI)m/e [M + 1]⁺ 405.9.

128 6-nitro-2-(4- phenoxyphenyl)- 4H-benzo[4,5] imidazo[1,2-b]pyrazole-3- carboxamide ¹H NMR (DMSO-d₆) δ 12.78 (s, 1H), 8.29 (s,1H), 8.14-8.08 (m, 1H), 8.04-7.96 (m, 1H), 7.91-7.81 (m, 2H), 7.49-7.39(m, 2H), 7.19 (t, J = 7.6 Hz, 1H), 7.15-7.05 (m, 4H). MS (ESI) m/e [M +1]⁺ 413.9.

129 6-amino-2-(4- phenoxyphenyl)- 4H-benzo[4,5] imidazo[1,2-b]pyrazole-3- carboxamide ¹H NMR (DMSO-d₆) δ 11.64 (s, 1H), 8.24 (s,1H), 7.73 (d, J = 8.8 Hz, 2H), 7.47-7.39 (m, 3H), 7.18 (t, J = 7.6 Hz,1H), 7.12-7.05 (m, 4H), 6.69 (d, J = 1.8 Hz, 1H), 6.50 (dd, J = 1.8, 8.8Hz, 1H), 5.21 (br s, 2H). MS (ESI) m/e [M + 1]⁺ 383.9.

130 6-acrylamido-2- (4-phenoxy- phenyl)-4H- benzo[4,5] imidazo[1,2-b]pyrazole-3- carboxamide ¹H NMR (CD₃OD-d₄) δ 8.14 (s, 1H), 7.68 (d, J =8.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.38-7.24 (m, 3H), 7.12-6.94 (m,5H), 6.46-6.25 (m, 2H), 5.71 (dd, J = 2.0, 9.6 Hz, 1H). MS (ESI) m/e[M + 1]⁺ 437.9.

131 8-amino-2-(4- phenoxyphenyl)- 4H-benzo[4,5] imidazo[1,2-b]pyrazole-3- carboxamide ¹H NMR (DMSO-d₆) δ 11.87 (s, 1H), 7.78 (d, J =8.4 Hz, 2H), 7.48-7.39 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.13-7.07 (m,4H), 7.02 (t, J = 8.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.50 (d, J =8.0 Hz, 1H), 5.56 (s, 2H). MS (ESI) m/e [M + 1]⁺ 383.9.

132 7-(1- acryloylazetidin- 3-yl)-2-(4-(3,4- dichlorophenoxy)phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide¹H NMR (DMSO-d₆) δ 7.61 (dd, J = 8.9, 2.8 Hz, 1H), 7.51 (d, J = 8.4 Hz,2H), 7.36 (d, J = 2.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 7.08-7.03 (m,1H), 6.66 (s, 1H), 6.35- 6.22 (m, 1H), 6.09-6.01 (m, 1H), 5.65-5.55 (m,1H), 4.40-4.30 (m, 2H), 4.29-4.21 (m, 0.5H), 4.15-4.06 (m, 1H),4.02-3.92 (m, 1H), 3.84-3.76 (m, 0.5H), 3.28-3.21 (m, 1H), 3.03-2.87 (m,1H), 2.21-2.00 (m, 1H), 1.77-1.66 (m, 1H). MS (ESI) m/e [M + ]⁺ 511.8,513.8.

133 7-(2- acrylamidophenyl)- 2-(3-methoxy-4- methylphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(DMSO-d₆) δ 9.82 (s, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.27 (t, J = 7.4 Hz,1H), 7.19 (d, J = 7.4 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 6.96 (s, 1H),6.93 (d, J = 7.4 Hz, 1H), 6.83 (s, 1H), 6.61 (d, J = 7.4 Hz, 1H), 6.50(dd, J = 17.1, 10.0 Hz, 1H), 6.24 (d, J = 17.1 Hz, 1H), 5.80-5.70 (m,2H), 3.74 (s, 3H), 3.28-3.19 (m, 1H), 2.99-2.87 (m, 1H), 2.33-2.19 (m,1H), 2.13 (s, 3H), 1.99-1.89 (m, 1H). MS (ESI) m/e [M + 1]⁺ 431.9.

133a (peak 1) (R or S) 7-(2- acrylamidophenyl)- 2-(3-methoxy-4-methylphenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3-carboxamide Chiral HPLC analysis condition: Instrument: Agilent 1260HPLC Column: CHIRALCEL OJ-H Column size: 0.46 cm I.D. × 15 cm L, 5 umMobile phase: n-Hexane/EtOH (0.1% triethyl amine) = 85/15 (v/v) Columntemperature: 35° C. Flow rate: 1.0 ml/min retention time: 5.86 min

133b (peak 2) (S or R) 7-(2- acrylamidophenyl)- 2-(3-methoxy-4-methylphenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3-carboxamide retention time: 6.64 min

134 7-(2- acrylamidophenyl)- 2-(4-chlorophenyl)- 4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ 9.81 (s,1H), 7.48 (d, J = 8.6 Hz, 2H), 7.45-7.38 (m, 3H), 7.27 (t, J = 7.2 Hz,1H), 7.17 (t, J = 7.2 Hz, 1H), 6.76 (s, 1H), 6.59 (d, J = 7.2 Hz, 1H),6.50 (dd, J = 17.0, 10.2 Hz, 1H), 6.24 (dd, J = 17.0, 1.8 Hz, 1H),5.79-5.67 (m, 2H), 3.26- 3.18 (m, 1H), 2.99-2.89 (m, 1H), 2.35-2.20 (m,1H), 1.99-1.88 (m, 1H). MS (ESI) m/e [M + 1]⁺ 421.8, 423.8.

134a (peak 1) (R or S) 7-(2- acrylamidophenyl)- 2-(4-chlorophenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ChiralHPLC analysis condition: Instrument: Agilent 1260 HPLC Column: CHIRALPAKAD-H Column size: 0.46 cm I.D. × 15 cm L, 5 um Mobile phase:n-Hexane/EtOH (0.1% triethyl amine) = 70/30 (v/v) Column temperature:35° C. Flow rate: 1.0 ml/min retention time: 4.15 min

134b (peak 2) (S or R) 7-(2- acrylamidophenyl)- 2-(4-chlorophenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide retentiontime: 10.52 min

135 7-(1- acryloylazetidin- 3-yl)-2-(4-(2- cyanophenoxy)phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide¹H NMR (DMSO-d₆) δ 7.91-7.85 (m, 1H), 7.71-7.61 (m, 1H), 7.58-7.52 (m,2H), 7.33- 7.24 (m, 1H), 7.20-7.14 (m, 2H), 7.11-7.05 (m, 1H), 6.61 (brs, 1H), 6.36-6.22 (m, 1H), 6.10-6.00 (m, 1H), 5.67-5.54 (m, 1H), 4.42-4.30 (m, 2H), 4.30-4.22 (m, 0.5H), 4.16- 4.07 (m, 1H), 403-3.92 (m, 1H),3.87-3.73 (m, 0.5H), 3.30-3.20 (m, 2H), 3.05-2.85 (m, 1H), 2.15-1.97 (m,1H), 1.78-1.64 (m, 1H). MS (ESI) m/e [M + 1]⁺ 468.9.

136 3-(1- acryloylpiperidin- 4-yl)-6-(4- phenoxyphenyl)- 1H-imidazo[1,2-b]pyrazole-7- carboxamide ¹H NMR (DMSO-d₆) δ 11.53 (s, 1H), 7.64 (d, J =8.4 Hz, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.14(t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H),6.96 (s, 1H), 6.80 (dd, J = 16.8, 10.1 Hz, 1H), 6.40 (brs, 2H), 6.07(dd, J = 16.8, 2.0 Hz, 1H), 5.64 (dd, J = 10.1, 2.0 Hz, 1H), 4.46 (d, J= 12.8 Hz, 1H), 4.10 (d, J = 12.8 Hz, 1H), 3.24-3.04 (m, 2H), 2.80 (t, J= 12.8 Hz, 1H), 2.20- 2.05 (m, 2H), 1.64-1.46 (m, 2H). MS (ESI) m/e [M +1]⁺ 455.9.

137 7-(2- acrylamidophenyl)- 2-(3,4-difluoro- phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ9.81 (s, 1H), 7.52- 7.36 (m, 3H), 7.34-7.24 (m, 2H), 7.17 (t, J = 7.6Hz, 1H), 6.74 (br s, 2H), 6.59 (d, J = 7.6 Hz, 1H), 6.50 (dd, J = 17.0,10.2 Hz, 1H), 6.24 (dd, J = 17.0, 1.6 Hz, 1H), 5.80- 5.70 (m, 2H),3.28-3.18 (m, 1H), 3.01-2.87 (m, 1H), 2.34-2.20 (m, 1H), 2.01-1.89 (m,1H). MS (ESI) m/e [M + 1]⁺ 423.9.

138 7-(1-acryloyl- piperidin-4-yl)-7- methyl-2-(4- phenoxyphenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(DMSO-d₆) δ 7.50 (d, J = 8.6 Hz, 2H), 7.45-7.37 (m, 2H), 7.17 (t, J =7.4 Hz, 1H), 7.11-7.03 (m, 4H), 6.85-6.72 (m, 1H), 6.68 (s, 1H), 6.07(dd, J = 16.7, 2.4 Hz, 1H), 5.64 (d, J = 10.6 Hz, 1H), 4.58-4.41 (m,1H), 4.19-4.00 (m, 1H), 3.33-3.24 (m, 2H), 3.05-2.85 (m, 1H), 2.60-2.50(m, 1H), 2.31-2.16 (m, 1H), 2.15-2.00 (m, 1H), 1.80- 1.65 (m, 2H), 1.44(s, 3H), 1.35-1.05 (m, 3H). MS (ESI) m/e [M + 1]⁺ 486.0.

139 7-(1- acryloylazetidin- 3-yl)-2-(3-chloro- 4-phenoxy-phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide¹H NMR (DMSO-d₆) δ 7.70-7.66 (m, 1H), 7.52-7.46 (m, 1H), 7.44-7.36 (m,2H), 7.19- 7.07 (m, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.66 (s, 1H),6.40-6.25 (m, 1H), 6.13-6.05 (m, 1H), 5.70-5.60 (m, 1H), 4.45-4.36 (m,2H), 4.33-4.26 (m, 0.5H), 4.21-4.08 (m, 1H), 4.07-3.95 (m, 1H),3.88-3.80 (m, 0.5H), 3.31-3.24 (m, 2H), 3.04-2.90 (m, 1H), 2.15- 2.04(m, 1H), 1.81-1.67 (m, 1H). MS (ESI) m/e [M + 1]⁺ 477.9.

140 7-(1- acryloylazetidin- 3-yl)-2-(3-methoxy- 4-phenoxy-phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamideformate ¹H NMR (CD₃OD-d₄) δ 8.38 (br s, 1H), 7.31-7.19 (m, 3H),7.15-7.10 (m, 1H), 7.06- 6.96 (m, 2H), 6.88 (d, J = 8.1 Hz, 2H),6.17-6.11 (m, 2H), 5.64-5.54 (m, 1H), 4.24- 4.08 (m, 2H), 4.06-3.95 (m,1H), 3.85-3.70 (m, 4H), 3.55-3.45 (m, 2H), 3.30-3.20 (m, 1H), 3.05-2.90(m, 1H), 2.48-2.36 (m, 1H), 1.40-1.25 (m, 1H). MS (ESI) m/e [M + 1]⁺473.9.

141 7-(1- acryloylazetidin- 3-yl)-2-(4-phenoxy- phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (CD₃OD-d₄)δ 7.41-7.35 (m, 2H), 7.32-7.24 (m, 4H), 7.22-7.15 (m, 1H), 7.03- 7.96(m, 2H), 6.31 (dd, J = 17.0, 10.2 Hz, 1H), 6.19 (dd, J = 17.0, 2.0 Hz,1H), 5.74- 5.66 (m, 1H), 4.55-4.26 (m, 3H), 4.25-3.94 (m, 4H), 3.48-3.34(m, 2H), 3.13-3.03 (m, 3H), 2.26-2.14 (m, 1H), 2.04-1.88 (m, 1H). MS(ESI) m/e [M + 1]⁺ 471.9.

142 7-(acrylamido- methyl)-2-(4- (benzyloxy)-3- methoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(DMSO-d₆) δ 8.31 (t, J = 6.0 Hz, 1H), 7.50-7.44 (m, 2H), 7.44-7.31 (m,3H), 7.17-7.05 (m, 2H), 7.04-6.99 (m, 1H), 6.72 (s, 1H), 6.26 (dd, J =17.1, 10.1 Hz, 1H), 6.11 (dd, J = 17.1, 1.8 Hz, 1H), 5.62 (dd, J = 10.1,1.8 Hz, 1H), 5.12 (s, 2H), 4.22- 4.12 (m, 1H), 3.85-3.72 (m, 4H),3.48-3.33 (m, 3H), 2.07-1.87 (m, 2H). MS (ESI) m/e [M + 1]⁺ 461.9.

143 7-(acrylamido- methyl)-7-methyl- 2-(4-phenoxy- phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (DMSO-d₆) δ8.08 (t, J = 6.4 Hz, 1H), 7.53-7.45 (m, 2H), 7.42-7.34 (m, 2H), 7.14 (t,J = 7.4 Hz, 1H), 7.08-7.00 (m, 4H), 6.66 (s, 1H), 6.29 (dd, J = 17.1,10.2 Hz, 1H), 6.08 (dd, J = 17.1, 2.2 Hz, 1H), 5.58 (dd, J = 10.2, 2.2Hz, 1H), 3.66 (dd, J = 13.5, 6.8 Hz, 1H), 3.47 (dd, J = 13.5, 6.8 Hz,1H), 2.05-1.94 (m, 1H), 1.79-1.69 (m, 1H), 1.38 (s, 3H). MS (ESI) m/e[M + 1]⁺ 431.9.

144 7-(1-acryloyl- piperidin-4-yl)-2- phenyl-4,5,6,7- tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide trifluoroacetate ¹H NMR(CD₃OD-d₄) δ 7.54-7.42 (m, 5H), 6.75 (dd, J = 16.8, 10.7 Hz, 1H), 6.15(dd, J = 16.8, 1.6 Hz, 1H), 5.70 (dd, J = 10.7, 1.6 Hz, 1H), 4.70-4.55(m, 1H), 4.25-4.00 (m, 2H), 3.50-3.40 (m, 2H), 3.14-3.03 (m, 1H),2.73-2.61 (m, 1H), 2.39-2.14 (m, 2H), 2.10-1.94 (m, 1H), 1.84-1.66 (m,2H), 1.51- 1.30 (m, 2H). MS (ESI) m/e [M + 1]⁺ 380.0.

145 7-(1-acryloyl- azetidin-3-yl)-2- (4-chlorophenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(DMSO-d₆) δ 7.50 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 6.62 (s,1H), 6.35-6.22 (m, 1H), 6.10-6.01 (m, 1H), 5.65- 5.55 (m, 1H), 4.40-4.21(m, 2.5H), 4.14- 4.06 (m, 1H), 4.04-3.90 (m, 1H), 3.85-3.75 (m, 0.5H),3.27-3.21 (m, 2H), 3.00-2.86 (m, 1H), 2.12-1.98 (m, 1H), 1.77-1.63 (m,1H).

146 7-(2- Acrylamidophenyl)- 2-(3-chloro-4- (pyridin-2-ylmethoxy)phenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3-carboxamide ¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 8.59 (d, J = 4.2Hz, 1H), 7.86 (dt, J = 7.6, 2.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.54(d, J = 2.0 Hz, 2H), 7.48-7.40 (m, 2H), 7.39-7.33 (m, 1H), 7.33-7.24 (m,2H), 7.21 (t, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H),6.53 (dd, J = 16.8, 10.2 Hz, 1H), 6.27 (dd, J = 16.8, 1.8 Hz, 1H), 5.82-5.74 (m, 2H), 5.30 (s, 2H), 3.30-3.20 (m, 1H), 3.02-2.92 (m, 1H),2.37-2.23 (m, 1H), 2.02-1.93 (m, 1H). MS (ESI) m/e [M + 1]⁺ 528.9.

147 7-(2- Acrylamido-4- chlorophenyl)-2- (4-(cyclopropyl-methoxy)phenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3-carboxamide MS (ESI) m/e [M + 1]⁺ 491.9.

148 7-(2- Acrylamido-4- methylphenyl)-2- (4-(cyclopropyl-methoxy)phenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3-carboxamide MS (ESI) m/e [M + 1]⁺ 471.9.

149 7-(2- Acrylamidophenyl)- 2-(4-(trifluoro- methoxy)phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 471.9.

150 7-(2- Acrylamidophenyl)- 2-phenyl-4,5,6,7- tetrahydro- pyrazolo[1,5-a]pyrimidine-3- carboxamide MS (ESI) m/e [M + 1]⁺ 387.9.

151 7-(2- Acrylamidophenyl)- 2-(4-fluoro- phenyl)-4,5,6,7- tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI) m/e [M + 1]⁺ 405.9.

152 7-(2- Acrylamidophenyl)- 2-(3-bromo-4- fluorophenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 7.77 (dd, J = 6.8, 2.0 Hz, 1H), 7.58-7.51 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 8.6 Hz, 1H), 7.31(t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.63 (d, J= 7.6 Hz, 1H), 6.53 (dd, J = 17.0, 10.2, Hz, 1H), 6.28 (dd, J = 17.0,1.8 Hz, 1H), 5.82-5.75 (m, 2H), 3.31-3.21 (m, 1H), 3.03- 2.91 (m, 1H),2.37-2.22 (m, 1H), 2.03-1.91 (m, 1H). MS (ESI) m/e [M + 1]⁺ 483.8,485.8.

153 (E)-2-(3-Chloro- 4-fluorophenyl)- 7-(2-(4- (piperidin-1- yl)but-2-enamido)phenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3-carboxamide MS (ESI) m/e [M + 1]⁺ 536.9.

154 7-(2- Acrylamidophenyl)- 2-(4-chloro-3- fluorophenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 7.65 (dd, J = 7.3, 2.0 Hz, 1H), 7.54-7.48 (m, 1H), 7.47-7.39 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.21 (t, J =7.6 Hz, 1H), 6.77 (s, 1H), 6.63 (d, J = 7.8 Hz, 1H), 6.53 (dd, J = 17.0,10.3 Hz, 1H), 6.27 (dd, J = 17.0, 1.8 Hz, 1H), 5.83-5.75 (m, 2H), 3.30-3.21 (m, 1H), 3.03-2.97 (m, 1H), 2.36-2.24 (m, 1H), 2.04-1.93 (m, 1H).MS (ESI) m/e [M + 1]⁺ 439.9.

155 7-(2- Acrylamidophenyl)- 2-(3-chlorophenyl)- 4,5,6,7-tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI) m/e [M + 1]⁺ 421.9.

156 7-(2- Acrylamidophenyl)- 2-(3,4-dichloro- phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR (400 MHz,DMSO-d₆) δ 9.83 (s, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 8.4 Hz,1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.31 (t,J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.63 (d, J =7.6 Hz, 1H), 6.53 (dd, J = 16.8, 10.2 Hz, 1H), 6.28 (d, J = 16.8 Hz,1H), 5.84-5.75 (m, 2H), 3.31-3.21 (m, 1H), 3.05- 2.92 (m, 1H), 2.38-2.23(m, 1H), 2.03-1.94 (m, 1H). MS (ESI) m/e [M + 1]⁺ 455.8.

157 7-(2- Acrylamidophenyl)- 2-(4-fluoro- 3-methyl- phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI) m/e [M +1]⁺ 419.9.

158 7-(2- Acrylamidophenyl)- 2-(3-chloro-4,5- difluorophenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 457.9.

159 7-(2- Acrylamidophenyl)- 2-(4-fluoro- 3-methoxy- phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI) m/e [M +1]⁺ 435.9.

160 7-(2- Acrylamidophenyl)- 2-(4-chloro- 3-methoxy- phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI) m/e [M +1]⁺ 451.8.

161 7-(2- Acrylamidophenyl)- 2-(4-trifluoro- methyl)phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 455.9.

162 7-(2- Acrylamidophenyl)- 2-(3-chloro-4- (trifluoromethyl)phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamideMS (ESI) m/e [M + 1]⁺ 489.8.

163 7-(2- Acrylamidophenyl)- 2-(4-chloro-3- (trifluoromethyl)phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamideMS (ESI) m/e [M + 1]⁺ 489.8.

164 7-(2- Acrylamidophenyl)- 2-(p-tolyl)-4,5,6,7- tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI) m/e [M + 1]⁺ 401.9.

165 (E)-7-(2-(4- (Dimethyl- amino)but-2- enamido)phenyl)-2-(3-methoxy-4- methylphenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrimidine-3- carboxamide MS (ESI) m/e [M + 1]⁺ 489.0.

166 7-(2- Acrylamidophenyl)- 2-(3-methoxy- phenyl)-4,5,6,7- tetrahydro-pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI) m/e [M + 1]⁺ 417.9.

167 7-(2- Acrylamidophenyl)- 2-(3,4,5- trimethoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 477.9.

168 7-(2- Acrylamidophenyl)- 2-(3,4- dimethoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 447.9.

169 7-(2- Acrylamidophenyl)- 2-(3,5-dichloro- 4-methoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 485.8.

170 (E)-2-(4- Phenoxyphenyl)- 7-(1-(4-(piperidin- 1-yl)but-2-enoyl)piperidin- 4-yl)-4,5,6,7- tetrahydro- pyrazolo[1,5-a]pyrimidine-3- carboxamide MS (ESI) m/e [M + 1]⁺ 569.0.

171 (R or S) (E)-7- (1-(4-(Dimethyl- amino)but-2- enoyl)piperidin-4-yl)-2-(4- phenoxyphenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrimidine-3- carboxamide MS (ESI) m/e [M + 1]⁺ 529.0.

172 7-(1- Acryloylpiperidin- 4-yl)-2-(3-methoxy- 4-phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 501.9.

173 7-(1- Acryloylpiperidin- 4-yl)-2-(3-chloro- 4-phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 505.9.

174 7-(1- Acryloylpiperidin- 4-yl)-2-(3-methoxy- 4-methylphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 424.0.

175 7-(1- Acryloylazetidin- 3-yl)-7-methyl-2- (4-phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 457.9.

176 (S)-7-(1-(But-2- ynoyl)piperidin- 4-yl)-2-(4- phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ 7.50 (d, J = 7.2 Hz, 2 H), 7.42 (dd, J = 8.4, 8.4Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.11-7.03 (m, 4H), 6.68 (s, 1 H),4.40-4.24 (m, 2 H), 4.06-3.97 (m, 1 H), 3.33-3.27 (m, 1 H), 3.12-3.00(m, 1 H), 2.66-2.54 (m, 1H), 2.32-2.20 (m, 1H), 2.07-2.00 (m, 1H), 2.00(s, 3 H), 1.96-1.86 (m, 1 H), 1.81-1.67 (m, 1 H), 1.63-1.52 (m, 1 H),1.36-1.08 (m, 2 H). MS (ESI) m/e [M + 1]⁺ 483.9.

177 (S)-7-(1-(3- chloropropanoyl) piperidin-4-yl)-2- (4-phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ 7.54- 7.47 (m, 2H), 7.45-7.38 (m, 2H), 7.21-7.14(m, 1H), 7.12-7.02 (m, 4H), 6.69 (s, 1H), 4.45 (d, J = 12.1 Hz, 1H),4.06-3.97 (m, 1H), 3.90 (t, J = 10.3 Hz, 1H), 3.82-3.72 (m, 2H),3.33-3.25 (m, 2H), 3.02-2.72 (m, 3H), 2.58-2.43 (m, 1H), 2.35-2.15 (m,1H), 2.10-1.84 (m, 2H), 1.70 (t, J = 12.1 Hz, 1H), 1.54 (t, J = 12.1 Hz,1H), 1.41-1.08 (m, 2H). MS (ESI) m/e [M + 1]⁺ 507.9, 509.9.

179 7-(1-(But-2- ynoyl)piperidin- 4-yl)-2-(4-(2,4- difluorophenoxy)phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide¹H NMR (400 MHz, DMSO-d₆) δ 7.55- 7.45 (m, 3H), 7.41-7.32 (m, 1H),7.21-7.12 (m, 1H), 7.05-6.99 (m, 2H), 6.67 (s, 1H), 4.39-4.22 (m, 2H),4.06-3.97 (m, 1H), 3.33- 3.25 (m, 2H), 3.12-2.97 (m, 1H), 2.69-2.52 (m,1H), 2.35-2.17 (m, 1H), 2.08-2.00 (m, 1H), 2.00 (s, 3H), 1.96-1.84 (m,1H), 1.81- 1.65 (m, 1H), 1.63-1.51 (m, 1H), 1.36-1.09 (m, 2H). MS (ESI)m/e [M + 1]⁺ 519.9.

180 (S)-7-(1-(2- Cyanoacetyl) piperidin-4-yl)-2- (4-phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 484.9.

183 7-(1- Acryloylpiperidin- 4-yl)-2-(4-(2,4- difluorophenoxy)phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide¹H NMR (400 MHz, DMSO-d₆) δ 7.58 7.44 (m, 3H), 7.41-7.30 (m, 1H),7.20-7.10 (m, 1H), 7.02 (d, J = 8.5 Hz, 2H), 6.85-6.73 (m, 1H), 6.67 (brs, 1H), 6.07 (d, J = 16.4 Hz, 1H), 5.64 (d, J = 10.5 Hz, 1H), 4.55- 4.39(m, 1H), 4.17-3.95 (m, 2H), 3.74-3.38 (m, 3H), 3.06-2.89 (m, 1H),2.35-2.15 (m, 1H), 2.09-1.83 (m, 2H), 1.78-1.65 (m, 1H), 1.62-1.49 (m,1H), 1.34-1.07 (m, 2H). MS (ESI) m/e [M + 1]⁺ 507.9.

184 7-(1-(But-2- ynoyl)azetidin- 3-yl)-2-(4- phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ 7.53- 7.46 (m, 2H), 7.45-7.38 (m, 2H), 7.21-7.13(m, 1H), 7.12-7.01 (m, 4H), 6.72-6.66 (m, 1H), 4.43-4.34 (m, 1H),4.33-4.27 (m, 0.5H), 4.26-4.15 (m, 1H), 4.11-4.04 (m, 1H), 4.02-3.92 (m,1H), 3.85-3.77 (m, 0.5H), 3.30-3.23 (m, 2H), 3.03-2.90 (m, 1H),2.15-2.04 (m, 1H), 2.00-1.90 (m, 3H), 1.82-1.67 (m, 1H). MS (ESI) m/e[M + 1]⁺ 455.9.

185 7-(1-(But-2- ynamidomethyl)-2- (4-phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ 8.67 (t, J = 6.0 Hz, 1H), 7.56-7.49 (m, 2H), 7.46-7.37 (m, 2H), 7.21-7.13 (m, 1H), 7.12-7.01 (m, 4H), 6.68 (s, 1H),4.20-4.09 (m, 1H), 3.76-3.65 (m, 1H), 3.36-3.24 (m, 3H), 2.09- 1.83 (m,5H). MS (ESI) m/e [M + 1]⁺ 429.9.

186 (S)-7-(1-(Pent- 2-ynoyl) piperidin-4-yl)-2- (4-phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ 7.50 (d, J = 8.1 Hz, 2H), 7.45-7.38 (m, 2H), 7.17(t, J = 7.4 Hz, 1H), 7.12-7.02 (m, 4H), 6.68 (s, 1H), 4.41-4.24 (m, 2H),4.09-3.97 (m, 1H), 3.33-3.26 (m, 2H), 3.14-2.99 (m, 1H), 2.68- 2.53 (m,1H), 2.43-2.33 (m, 2H), 2.31-2.19 (m, 1H), 2.07-1.83 (m, 2H), 1.82-1.66(m, 1H), 1.63-1.50 (m, 1H), 1.40-1.13 (m, 2H), 1.11 (t, J = 7.5 Hz, 3H).MS (ESI) m/e [M + 1]⁺ 498.0.

187 (S)-2-(4- Phenoxyphenyl)- 7-(1-(4- (pyrrolidin-1- yl)but-2-ynoyl)piperidin-4-yl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3-carboxamide ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (d, J = 8.2 Hz, 2H),7.45-7.37 (m, 2H), 7.17 (t, J = 7.4 Hz, 1H), 7.11-7.02 (m, 4H), 6.67 (s,1H), 4.41-4.22 (m, 2H), 4.08-3.99 (m, 1H), 3.69 (s, 2H), 3,18-3.04 (m,1H), 2.75-2.55 (m, 5H), 2.35-2.20 (m, 1H), 2.09-1.85 (m, 2H), 1.83-1.66(m, 5H), 1.66-1.53 (m, 1H), 1.40-1.11 (m, 4H). MS (ESI) m/e [M + 1]⁺553.0.

188 (S)-7-(1-(4- (Dimethyl- amino)but-2- ynoyl)piperidin-4-yl)-2-(4-phenoxy- phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5-a]pyrimidine-3- carboxamide ¹H NMR (400 MHz, DMSO-d₆) δ 7.53- 7.47 (m,2H), 7.46-7.38 (m, 2H), 7.20-7.14 (m, 1H), 7.12-7.02 (m, 4H), 6.69-6.64(m, 1H), 4.45-4.23 (m, 2H), 4.08-3.99 (m, 1H), 3.52 (s, 2H), 3.19-3.05(m, 1H), 2.72-2.57 (m, 1H), 2.54-2.49 (m, 1H), 2.36-2.18 (m, 7H),2.10-1.86 (m, 2H), 1.83-1.68 (m, 1H), 1.67-1.53 (m, 1H), 1.41-1.11 (m,3H). MS (ESI) m/e [M + 1]⁺ 527.0.

189 7-(1-(But-2- ynoyl)azetidin- 3-yl)-2-(4-(2,4- difluoro-phenoxy)phenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3-carboxamide MS (ESI) m/e [M + 1]⁺ 491.9.

190 7-(But-2- ynamidomethyl)- 2-(4-(2,4- difluoro- phenoxy)phenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide MS (ESI)m/e [M + 1]⁺ 465.9.

191 (S)-7-(1-(4- Hydroxybut-2- ynoyl)piperidin- 4-yl)-2-(4-phenoxyphenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3-carboxamide MS (ESI) m/e [M + 1]⁺ 499.9.

192 (S)-7-(1-(4- Methoxybut-2- ynoyl)piperidin- 4-yl)-2-(4-phenoxyphenyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3-carboxamide ¹H NMR (400 MHz, DMSO-d₆) δ 7.54- 7.47 (m, 2H), 7.45-7.38(m, 2H), 7.21-7.14 (m, 1H), 7.12-7.03 (m, 4H), 6.69 (s, 1H), 4.41-4.32(m, 1H), 4.30 (s, 2H), 4.29-4.20 (m, 1H), 4.09-3.98 (m, 1H), 3.33-3.26(m, 2H), 3.29 (s, 3H), 3.19-3.05 (m, 1H), 2.72- 2.57 (m, 1H), 2.36-2.21(m, 1H), 2.09-1.98 (m, 1H), 2.09-1.97 (m, 1H), 1.84-1.68 (m, 1H),1.66-1.50 (m, 1H), 1.41-1.10 (m, 2H). MS (ESI) m/e [M + 1]⁺ 514.0.

193 (S)-7-(1-(Hex-2- ynoyl)piperidin- 4-yl)-2-(4- phenoxyphenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ 7.54- 7.48 (m, 2H), 7.45-7.38 (m, 2H), 7.21-7.14(m, 1H), 7.12-7.02 (m, 4H), 6.68 (s, 1H), 4.42-4.22 (m, 2H), 4.06-3.98(m, 1H), 3.33- 3.25 (m, 2H), 3.15-3.01 (m, 1H), 2.69-2.53 (m, 1H), 2.36(t, J = 6.9 Hz, 2H), 2.32-2.20 (m, 1H), 2.08-1.97 (m, 1H), 1.97-1.84 (m,1H), 1.83-1.67 (m, 1H), 1.65-1.46 (m, 3H), 1.38-1.09 (m, 3H), 0.94 (t, J= 7.4 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 512.0.

194 7-(1-(But-2- ynoyl)piperidin- 4-yl)-2-(4-(4- fluorophenoxy)phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide¹H NMR (400 MHz, DMSO-d₆) δ 7.53- 7.46 (m, 2H), 7.30-7.21 (m, 2H),7.18-7.11 (m, 2H), 7.07-7.00 (m, 2H), 6.64 (br s, 1H), 4.39-4.23 (m,2H), 4.06-3.98 (m, 1H), 3.34- 3.26 (m, 2H), 3.12-2.99 (m, 1H), 2.69-2.53(m, 1H), 2.31-2.18 (m, 1H), 2.08-2.01 (m, 1H), 2.00 (s, 3H), 1.97-1.86(m, 1H), 1.81- 1.66 (m, 1H), 1.64-1.51 (m, 1H), 1.36-1.08 (m, 2H). MS(ESI) m/e [M + 1]⁺ 501.9.

195 7-(1-(But-2- ynoyl)piperidin- 4-yl)-2-(4-(3- chlorophenoxy)phenyl)-4,5,6,7- tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide¹H NMR (400 MHz, DMSO-d₆) δ 7.57- 7.50 (m, 2H), 7.46-7.39 (m, 1H),7.25-7.20 (m, 1H), 7.17-7.10 (m, 3H), 7.08-7.02 (m, 1H), 6.63 (br s,1H), 4.40-4.22 (m, 2H), 4.06-3.98 (m, 1H), 3.34-3.26 (m, 2H), 3.13- 3.00(m, 1H), 2.69-2.54 (m, 1H), 2.31-2.19 (m, 1H), 2.08-2.00 (m, 1H), 2.00(s, 3H), 1.96-1.87 (m, 1H), 1.82-1.66 (m, 1H), 1.64- 1.52 (m, 1H),1.35-1.09 (m, 2H). MS (ESI) m/e [M + 1]⁺ 517.9, 519.9.

196 7-(2- Acrylamidophenyl)- 2-(3-chloro-4- fluorophenyl)-4,5,6,7-tetrahydro- pyrazolo[1,5- a]pyrimidine-3- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ 9.82 (s, 1H), 7.65 (dd, J = 7.4, 2.1 Hz, 1H), 7.55-7.47 (m, 1H), 7.47-7.38 (m, 2H), 7.31 (t, J = 7.1 Hz, 1H), 7.34-7.28 (m,1H), 6.76 (br s, 1H), 6.63 (d, J = 7.4 Hz, 1H), 6.53 (dd, J = 17.2, 10.3Hz, 1H), 6.27 (dd, J = 17.2, 1.9 Hz, 1H), 5.83-5.73 (m, 2H), 3.30-3.22(m, 1H), 3.03-2.93 (m, 1H), 2.37-2.24 (m, 1H), 2.03-1.93 (m, 1H). MS(ESI) m/e [M + 1]⁺ 439.8, 441.8.

BTK Kinase Assay

Compounds disclosed herein were tested for inhibition of Btk kinaseactivity in an assay based on time-resolved fluorescence resonanceenergy transfer methodology. Recombinant Btk was pre-incubated with thecompounds disclosed herein at room temperature for 1 hour in an assaybuffer containing 50 mM Tris pH7.4, 10 mM MgCl₂, 2 mM MnCl₂, 0.1 mMEDTA, 1 mM DTT, 20 nM SEB, 0.1% BSA, 0.005% tween-20. The reactions wereinitiated by the addition of ATP (at the concentration of ATP Km) andpeptide substrate (Biotin-AVLESEEELYSSARQ-NH2). After incubating at roomtemperature for 1 h, an equal volume of stop solution containing 50 mMHEPES pH7.0, 800 mM KF, 20 mM EDTA, 0.1% BSA, Eu cryptate-conjugatedp-Tyr66 antibody and streptavidin-labeled XL665 was added to stop thereaction. Plates were further incubated at room temperature for 1 hour,and then the TR-FRET signals (ex337nm, em 620 nm/665 nm) were read onBMG PHERAstar FS instrument. The residual enzyme activity in presence ofincreasing concentrations of compounds was calculated based on the ratioof fluorescence at 615 nm to that at 665nm. The IC₅₀ for each compoundwas derived from fitting, the data to the four-parameter logisticequation by Graphpad Prism software.

BTKpY223 Cellular Assay

Btk pY223 cellular assay is a HTRF based assay intended to determine theendogenous levels of phosphorylated Btk at Tyr223. Phosphorylated Tyr223is necessary for full activation of Btk. The assay was performed inRamos cells (CRL-1596, ATCC) with a Btk pY223 assay kit (63IDC000.Cisbio).

Briefly, Ramos cells were serum starved in 0.5% FBS-containing RPM11640for 2 hours. Following starvation, the cells were incubated withcompounds, to be detected at various concentrations in a CO2 incubatorfor 1 hour. After incubation, cells were stimulated with 1 mMpervanadate (PV) or Na₃VO₄ (OV) for 20 min. Then, the cells were spinneddown and lysed with 1× lysis buffer at RT for 10 min (4× lysis buffersupplied in the kit). During the incubation, 1× antibody mix wasprepared by diluting anti-Btk-d2 and anti-pBtk-K in detection buffer(supplied in the kit). 2 ul/well of 1× antibody mixture was dispensedinto the OptiPlate-384 assay plate (6005620, Perkin Elmer). After that,18 ul of cell lysate was transferred to the assay plate pre-loaded withantibody solution. After mixing gently and spinning briefly, the platewas sealed up and kept in dark at RT for 18 hours. The fluorescenceemission was measured at two different wavelengths (665 nm and 620 nm)on a compatible HTRF reader (PHERAstar FS, BMG). The potency ofcompounds was calculated basing on the inhibition of ratio betweensignal intensities at 665 nm and 620 nm. IC50 values were calculatedwith GraphPad Prism software using the sigmoidal dose-response function.

Representative compounds as disclosed herein were tested and found toinhibit Btk and autophosphorylation of Btk at Tyr-223 with IC50 valuesranging from subnanomolar to 10 micromolar.

TABLE II Assay data for representative compounds IC50 (nM) Compound No.Btk Btk pY223 1 >10,000 n.d. 2 360 n.d. 2a (peak 1) 270 n.d. 2b (peak 2)210 n.d. 3 3.6 12.7 3a (peak 1) 2.5 8.7 3b (peak 2) 1.7 2.0 4 26 n.d. 5200 n.d. 6 0.71 3.1 6a (peak 1) 0.4 3.0 6b (peak 2) 120 n.d. 7 >10,000n.d. 8 860 n.d. 9 3,700 n.d. 10 1.5 8.0 10a (peak 1) 0.51 2.2 10b (peak2) 42 n.d. 11 4,500 n.d. 12 1.7 23.6 13 1000 n.d. 14 4.7 232.6 15 2,700n.d. 16 19 n.d. 17 >10,000 n.d. 18 1.3 26.3 19 5,300 n.d. 20 1.6 12.620a (peak 1) 1.2 2.5 20b (peak 2) 110 n.d. 21 >10,000 n.d. 22 2.7 16.723 3,200 n.d. 24 39 n.d. 25 3,100 n.d. 26 1700 n.d. 27 1 4.6 27a(peak 1) 0.33 5.7 27b (peak 2) 2 20.0 28 3,400 n.d. 29 0.48 18 29a(peak 1) 0.43 1.6 29b (peak 2) 1.3 4.1 30 1 4.0 30a (peak 1) 0.66 5.630b (peak 2) 16 n.d. 31 15 n.d. 32 1,700 n.d. 33 0.9 2.9 33a (peak 1)0.6 5.9 33b (peak 2) 11 63.3 34 1,900 n.d. 35 1.1 7.9 36 >10,000 n.d. 37640 n.d. 38 490 n.d. 39 1,400 n.d. 40 13 n.d. 41 180 n.d. 42 330 n.d. 433.0 75.8 44 220 n.d. 45 510 n.d. 46 5 22.6 47 110 n.d. 48 150 n.d. 49 29n.d. 50 2.7 8.0 51 310 n.d. 52 0.14 <0.5 53 7.7 n.d. 54 0.19 6.4 55 82n.d. 56 110 n.d. 57 37 232.9 58 0.43 4.6 59 43 n.d. 60 40 n.d. 61 140n.d. 62 240 n.d. 63 0.18 1.5 64 0.17 4.8 65 320 n.d. 66 14 322.2 67 0.322.8 68 190 n.d. 69 7.8 34.4 70 19 n.d. 71 55 n.d. 72 4.1 10.5 73 >10,000n.d. 74 240 n.d. 75 41 222.9 76 5,500 n.d. 77 480 n.d. 78 21 139.6 79 50n.d. 80 >10,000 n.d. 81 5,900 n.d. 82 3,100 n.d. 83 130 n.d. 84 2,900n.d. 85 32 73.2 86 2.2 4.4 87 2,000 n.d. 88 16.0 n.d. 89 >10,000 n.d. 901,900 n.d. 91 1,900 n.d. 92 1.1 7.0 93 1,500 n.d. 94 1.9 6.7 95 470 n.d.96 30 n.d. 97 1.1 n.d. 98 77 n.d. 99 9.5 43.4 100 260 n.d. 101 550 n.d.102 830 n.d. 103 1.1 14 104 2.6 20.6 105 18 n.d. 106 1.4 30.3 107 0.4811.2 108 3.5 18.9 109 41 n.d. 110 3,000 n.d. 111 24 n.d. 112 >10,000n.d. 113 94 n.d. 114 6,000 n.d. 115 8,200 n.d. 116 1 3.2 117 34 n.d. 118410 n.d. 119 40 n.d. 120 180 n.d. 121 0.36 8.2 122 0.78 12.6 123 0.151.5 124 0.62 4.6 125 5,000 n.d. 126 20 n.d. 127 300 n.d. 128 930 n.d.129 23 n.d. 130 14 n.d. 131 170 n.d. 132 1.7 6.2 133 0.53 1.8 133a(peak 1) 0.23 2.9 133b (peak 2) 16 n.d. 134 0.78 4.7 134a (peak 1) 0.644.2 134b (peak 2) 1500 n.d. 135 0.38 2.4 136 0.13 0.8 137 3.2 22.7 1381.0 7.6 139 0.44 3.1 140 3000 n.d. 141 7.0 n.d. 142 54 n.d. 143 0.89 4.1144 140 n.d. 145 72 n.d. 146 1.3 4.0 147 2.7 n.d. 148 5.6 n.d. 149 4.2n.d. 150 4.7 n.d. 151 1.9 2.5 152 1.2 1.8 153 6.1 165.2 154 1.2 1.5 1550.96 n.d. 156 0.55 6.8 157 0.38 20 158 2.9 n.d. 159 1 4.5 160 0.49 1.3161 4.2 n.d. 162 2.1 3.2 163 7.3 n.d. 164 1.6 3.9 165 1.6 19.1 166 2.7n.d. 167 2.4 n.d. 168 3.2 n.d. 169 0.15 7 170 3.8 33.7 171 1.4 10.9 1721.1 0.8 173 0.81 2.1 174 4.8 n.d. 175 1.2 17.6 176 3 15.1 177 5.7 3.9178 46 >1000 179 48 n.d. 180 87 n.d. 181 25 n.d. 182 124 n.d. 183 1.22.9 184 4.7 6.7 185 4.3 4.4 186 1.1 10.3 187 2.1 7.3 188 1.1 8.5 189 42n.d. 190 38 n.d. 191 0.67 n.d. 192 0.91 n.d. 193 3.9 n.d. 194 45 n.d.195 8.0 n.d. 196 1.1 2.0 n.d.: No data.

TABLE III

What is claimed is:
 1. A method for modulating Bruton's tyrosine kinaseactivity in a patient suffering from a B-cell proliferative disorder,comprising administering to the patient a therapeutically effectiveamount of a compound of formula I:

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: A is a 5- or 6-membered aromatic ring comprising 0, 1, 2, or 3heteroatoms selected from the group consisting of nitrogen, sulfur, andoxygen; W is —(CH₂)— or —C(O)—; L is a bond, CH_(2,) NR¹², O, or S; S/Dis a single or double bond, wherein when S/D is a double bond, R⁵ and R⁷are absent; m is 1; n is 0, 1, 2, 3, or 4, wherein when n is 2, 3, or 4,each R² may be different; p is 1; R^(1,) R⁴, R⁵, R⁶ and R⁷ are eachindependently H, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl,saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN,—NR¹³R¹⁴, —OR¹³, —COR¹³, —CO₂R¹³, —CONR¹³R¹⁴, —C(═NR¹³)NR¹⁴R¹⁵,—NR¹³COR¹⁴, —NR¹³CONR¹⁴R¹⁵, —NR¹³CO₂R¹⁴, —SO₂R¹³, —NR¹³SO₂NR¹⁴R¹⁵, or—NR¹³SO₂R¹⁴, wherein the alkyl, alkenyl, alkynyl, cycloalkyl,heteroaryl, aryl, and saturated or unsaturated heterocyclyl areoptionally substituted with at least one substituent R¹⁶; R² is halogen,alkyl, —S-alkyl, —CN, —NR¹³R¹⁴, —OR¹³, —COR¹³, —CO₂R¹³, —CONR¹³R¹⁴,—C(═NR¹³)NR¹⁴R¹⁵, —NR¹³COR¹⁴, —NR¹³CONR¹⁴R¹⁵, —NR¹³CO₂R¹⁴, —SO₂R¹³,—NR¹³SO₂NR¹⁴R¹⁵, or —NR¹³SO₂R¹⁴; R¹² is H or lower alkyl; R¹³, R¹⁴ andR¹⁵ are each independently H, heteroalkyl, alkyl, alkenyl, alkynyl,cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heteroaryl;wherein (R¹³ and R¹⁴), and/or (R¹⁴ and R¹⁵) together with the atom(s) towhich they are attached, may independently form a ring selected fromcycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heteroaryl,each optionally substituted with at least one substituent R¹⁶; and R¹⁶is halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, oxo, —CN, —OR′, —NR′R″, —COR′, —CO₂R′, —CONR′R″,—C(=NR′)NR″R″′, —NR′COR″, —NR′CONR′R″, —NR′CO₂R″, —SO₂R′, —SO₂aryl,—NR′SO₂NR″R″′, or —NR′SO₂R″, wherein R′, R″, and R″′ are independentlyH, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl, wherein (R′ and R″) and/or (R″ and R″′) together with theatom(s) to which they are attached, may independently form a ringselected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; whereineach alkyl, alkenyl and alkynyl of R¹⁶, R′, R″, and R′″ is optionallysubstituted with at least one substituent selected from the groupconsisting of halogen, cycloalkyl, aryl, heteroaryl, heterocyclyl, oxo,—CN, —OR^(a), —NR^(a)R^(b), —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),—C(═NR^(a))NR^(b)R^(c), —NR^(a)COR^(b), —NR^(a)CONR^(a)R^(b),—NR^(a)CO₂R^(b), —SO₂R^(a), —SO₂aryl, —NR^(a)SO₂NR^(b)R^(c), and—NR^(a)SO₂R^(b); wherein each cycloalkyl, aryl, heteroaryl, andheterocyclyl of R¹⁶, R′, R″, and R″′ is optionally substituted with atleast one substituent selected from the group consisting of halogen,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,oxo, —CN, —OR^(a), —NR^(a)R^(b), —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),—C(═NR^(a))NR^(b)R^(c), —NR^(a)COR^(b), —NR^(a)CONR^(a)R^(b),—NR^(a)CO₂R^(b), —SO₂R^(a), —SO₂aryl, —NR^(a)SO₂NR^(b)R^(c), and—NR^(a)SO₂R^(b); and wherein each R^(a), R^(b), and R^(c) isindependently selected from the group consisting of H, halogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.
 2. Themethod of claim 1, wherein the B-cell proliferative disorder is selectedfrom a chronic lymphocytic lymphoma, non-Hodgkin's lymphoma, diffuselarge B-cell lymphoma, mantle cell lymphoma, follicular lymphoma orchronic lymphocytic leukemia.
 3. The method of claim 1, wherein S/D is asingle bond.
 4. The method of claim 1, wherein A is a phenyl.
 5. Themethod of claim 1, wherein L is O.
 6. The method of claim 1, wherein R¹is aryl, optionally substituted with at least one substituent R¹⁶. 7.The method of claim 1, wherein each R² is independently halogen, loweralkyl, or lower alkoxy.
 8. The method of claim 1, wherein R⁴ is


9. The method of claim 1, wherein R⁴ is


10. The method of claim 1, wherein R⁵, R⁶ and R⁷ are each independentlyH.
 11. The method of claim 1, wherein W is —(CH₂)—.
 12. The method ofclaim 1, wherein the compound is of formula II:


13. The method of claim 1, wherein the compound is


14. The method of claim 1, wherein the compound is


15. The method of claim 1, wherein the compound is